Substituted oxotremorine derivatives

ABSTRACT

This disclosure describes novel substituted oxotremorine derivatives of formula I having nitrogen, oxygen or sulfur groups and the prodrug forms of these derivatives. The compounds have cholinergic activity. Also disclosed are methods for treating diseases of the central nervous system in mammals employing the compounds, pharmaceutical preparations containing the compounds and the processes for the production of the compounds. ##STR1##

CONTROL REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of application Ser. No.274,604 filed on Jul. 13, 1994 which is a divisional of Ser. No. 690,749filed Apr. 24, 1991 now U.S. Pat. No. 5,356,885.

BACKGROUND OF INVENTION

The invention relates to compounds, pharmaceutical compositions and tothe use of the compounds for the manufacture of pharmaceuticals.

A chronic deficiency in central cholinergic function has been implicatedin a variety of neurologic and psychiatric disorders, including seniledementia of the Alzheimer's type (SDAT), tardive dyskinesia, Pick'sdisease and Huntington's chorea. Postmortem neurochemical investigationsof patients with SDAT have demonstrated a reduction in presynapticmarkers for acetylcholine utilizing neurons in the hippocampus and thecerebral cortex [P. Davies and A. J. R. Maloney, Lancet, 1976, 1403,(1976); E. K. Perry, R. H. Perry, G. Blessed, B. E. Tomlinson, J.Neurol. Sci., 34, 247, (1976)]. The basis for the cholinergicabnormality is unclear, but evidence suggests that the cholingergicneurons in the nucleus basalis of Meynert may selectively degenerate inSDAT [J. T. Coyle, D. J. Price, M. R. DeLong, Science, 219, 1184,(1983)]. If this degeneration plays a role in behavior symptoms of thedisease, then a possible treatment strategy would be to compensate forthe loss of cholinergic output to the cortex and hippocampus.

In an aged monkey animal model, designed to mimic the symptoms of SDAT,the direct muscarinic agonists arecoline [R. T. Bartus, R. L. Dean, B.Beer, Neurobiology of Aging, 1, 145, (1980)] and oxotremorine [R. T.Bartus, R. L. Dean, B. Beer, Psychopharmacology Bulletin, 19, 168,(1983)] produced significant improvement in performance. These resultsin aged monkeys were corroborated in SDAT patients with arecoline whichproduced a more consistent improvement when compared to theanticholinergic inhibitor physostigmine [J. E. Christie, A. Shering, J.Ferguson, A. M. Glen, British Journal of Psychiatry, 138, 46, (1981)].

These animal behavioral and clinical results have instigated significantefforts in a search for a muscarinic agonist which will selectivelycompensate for the loss of cholinergic input in the hippocampus andcerebral cortex. However, the search must be refined to seek agonistswhich will not affect significantly the remaining body cholinergicfunctions. The recent disclosure that muscarinic receptors are not allthe same but exist as a heterogeneous population of receptorssubstantiates the possibility for the discovery of a selectivemuscarinic agonist [T. I. Bonner, N. J. Buckley, A. C. Young, M. R.Brann, Science, 237, 527, (1987)].

The methodical methylation of the muscarinic agonist oxotremorine andits derivatives has been studied in the search for a selectivemuscarinic agonist [B. Ringdahl, J. Med. Chem., 31, 683, (1988); B.Ringdahl, "Structural Determinants of Muscarinic Agonist Activity" TheMuscarinic Receptors, J. H. Brown Ed., The Humana Press, Clifton, N.J.,1989, 151]. The methodical substitution of a methyl group ontooxotremorine can probe the steric non-polar environment of themuscarinic agonist for its neurotransmitter-receptor-complex.

The present invention describes the preparation of oxotremorinederivatives having polar substituted oxygen and substituted sulfurgroups. This series of compounds goes beyond the initial study byRingdall. In addition to exploring the steric environment of themuscarinic agonist for its neurotransmitter complex, the compounds ofthe present invention probe possible auxiliary polar interactions withone of the muscarinic receptors.

SUMMARY OF THE INVENTION

This invention is concerned with new compounds of formula I which havecholinergic activity; with methods of treating diseases of the centralnervous system in mammals employing these new compound; withpharmaceutical preparations containing these compound; and withprocesses for the production of these compounds. ##STR2## wherein R₁ andR₂ are each independently selected from the group consisting of (C₁-C₆)alkyl and (C₃ -C₇)cycloalkyl; or

one of R₁ and R₂ is (C₁ -C₆)alkyl and the other is --(CH₂)_(n) R₁₇, andn is 2 to 6; or

R₁ and R₂ when taken together with the associated N(itrogen) atom isimidazole or may form a moiety of formula II: ##STR3## A is carbon,nitrogen, oxygen or sulfur; m is 0, 1 or 2;

R₉, R₁₀ are hydrogen; hydroxymethyl;

(C₁ -C₆)trialkylsilyloxymethyl, halomethyl, wherein halo is Cl, Br, I;or alkyl- aryl- or substituted arylsulfonylmethyl;

with the proviso that when m is 0 or 1, and R₇, R₈, R₉, R₁₀ are otherthan hydrogen, A is carbon;

wherein

R₃, R₄, R₅, R₆, R₇, R₈, R₁₇ are selected from hydrogen, amino,substituted amino, mono(C₁ -C₆)alkylamino, substituted mono(C₁-C₆)alkylamino, di(C₁ -C₆)alkylamino, azido, hydroxy, substitutedhydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkyloxymethyleneoxy, aryl(C₁-C₄)alkyloxymethyleneoxy, substituted aryl(C₁ -C₄)alkyloxymethyleneoxy,(C₁ -C₁₀ )acyloxymethyleneoxy, aroyloxymethyleneoxy, substitutedaroyloxymethyleneoxy, thio, substituted thio, (C₁ -C₆)alkylthio, (C₁-C₆)alkyldithio, and (C₁ -C₆)trialkylsilyloxy;

wherein

the aforesaid substituted amino or substituted mono(C₁ -C₆)alkylaminomoieties may be substituted with a carbonyl moiety selected from (C₁-C₁₀)acyl, (C₃ -C₇)cycloalkylcarbonyl, (C₃ -C₇)cycloalkyl[(C₁-C₄)alkyl]carbonyl, heterocycloalkylcarbonyl, aroyl, aryl(C₁-C₄)alkyl-carbonyl, heteroaroyl, heteroaryl(C₁ -C₄)alkylcarbonyl, (C₁-C₁₀)alkoxycarbonyl, (C₃ -C₇)cycloalkoxycarbonyl, (C₃ -C₇)cycloalkyl[(C₁-C₄)alkoxy]carbonyl, heterocycloalkoxycarbonyl, heterocycloalkyl[C.sub.₁-C₄)alkoxy]carbonyl, aryloxycarbonyl, aryl(C₁ -C₄)alkoxycarbonyl, andheteroaryl(C₁ -C₄)alkoxycarbonyl;

wherein

the aforesaid substituted hydroxy moieties may be substituted with acarbonyl moiety selected from (C₁ -C₁₀)acyl, (C₃ -C₇)cycloalkylcarbonyl,(C₃ -C₇)cycloalkyl[(C₁ -C₄)alkyl]carbonyl, heterocycloalkylcarbonyl,aroyl, aryl(C₁ -C₄)alkylcarbonyl, heteroaroyl, substituted heteroaroyl,heteroaryl(C₁ -C₄)alkylcarbonyl, (C₁ -C₁₀)alkoxycarbonyl, (C₃-C₇)cycloalkoxycarbonyl, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkoxy]carbonyl,heterocycloalkyloxycarbonyl, heterocycloalkyl[(C₁ -C₄)alkoxy]carbonyl,aryloxycarbonyl, aryl(C₁ -C₄)alkyloxycarbonyl, heteroaryl(C₁-C₄)alkoxycarbonyl, (C₁ -C₁₀)alkylaminocarbonyl, (C₃-C₇)cycloalkylaminocarbonyl, (C₃ -C₇)cycloalkyl[(C₁-C₄)alkyl]aminocarbonyl, heterocycloalkylaminocarbonyl,arylaminocarbonyl, aryl(C₁ -C₄)alkylaminocarbonyl,heteroarylaminocarbonyl, heteroaryl(C₁ -C₄)alkylaminocarbonyl, (C₁-C₁₀)dialkylaminocarbonyl, aryl[(C₁ -C₄)alkyl]aminocarbonyl, (C₃-C₇)cycloalkylalkylaminocarbonyl, diarylaminocarbonyl, and bis[aryl(C₁-C₄)alkyl]aminocarbonyl;

wherein

the aforesaid substituted thio moiety may be substituted with a carbonylmoiety selected from (C₁ -C₁₀)acyl, (C₃ -C₇)cycloalkylcarbonyl, (C₃-C₇)cycloalkyl[(C₁ -C₄)alkyl]carbonyl, heterocycloalkylcarbonyl, aroyl,aryl(C₁ -C₄)alkylcarbonyl, heteroarylcarbonyl, heteroaryl(C₁-C₄)alkylcarbonyl, (C₁ -C₁₀)alkoxycarbonyl, (C₃ -C₇)cycloalkoxycarbonyl,(C₃ -C₇)cycloalkyl[(C₁ -C₄)alkoxy]carbonyl, heterocycloalkyloxycarbonyl,heterocycloalkyl[(C₁ -C₄)alkoxy]carbonyl, aryloxycarbonyl, aryl(C₁-C₄)alkyloxycarbonyl, heteroaryl(C₁ -C₄)alkoxycarbonyl, (C₁-C₁₀)alkylaminocarbonyl, (C₃ -C₇)cycloalkylaminocarbonyl, (C₃-C₇)cycloalkyl[(C₁ -C₄)alkyl]aminocarbonyl,heterocycloalkylaminocarbonyl, arylaminocarbonyl, aryl(C₁-C₄)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C₁-C₄)alkylaminocarbonyl, (C₁ -C₁₀)dialkylaminocarbonyl, aryl[(C₁-C₄)alkyl]aminocarbonyl, C₄ -C₇)cycloalkylalkylaminocarbonyl,diarylaminocarbonyl, and bis[aryl(C₁ -C₄)alkyl]aminocarbonyl;

wherein

either R₃ or R₄ may also be selected from (C₁ -C₆)alkyl with the provisothat:

the other must be selected from hydrogen, hydroxy, substituted hydroxy;

R₅ and R₆ must be hydrogen;

R₁ and R₂ independently may not be (C₁ -C₆)alkyl, (C₃ -C₇)cycloalkyl; or

R₁ and R₂ taken together with the associated N(itrogen) atom may not beazetidine, pyrrolidine or piperidine;

with the proviso that:

if there is a substituent at R₇, R₈, R₉ or R₁₀ then the other of thesesubstituents must be hydrogen;

A must be carbon; and

m must be 1;

with the proviso that:

if there is a hydroxy, substituted hydroxy, (C₁ -C₆)alkoxy, (C₁-C₆)alkyloxymethyleneoxy, aryl(C₁ -C₄)alkyloxymethyleneoxy, substitutedaryl(C₁ -C₄)alkyloxymethyleneoxy, (C₁ -C₁₀)acyloxymethyleneoxy,aroyloxymethyleneoxy, substituted aroyloxymethyleneoxy or (C₁ -C₆)trialkylsilyloxy substituent at R₃ or R₄ ;

the other substituent must be either hydrogen or (C₁ -C₆)alkyl;

and R₅ and R₆ must be hydrogen;

or if there is an amino, substituted amino, mono(C₁ -C₆)alkylamino,substituted mono(C₁ -C₆)alkylamino, di(C₁ -C₆)alkylamino, azido, thio,substituted thio, (C₁ -C₆)alkylthio, or (C₁ -C₆)alkyldithio substituentat R₃ or R₄ ;

the other substituent must be hydrogen;

with the proviso that:

if there is a substituent other than hydrogen at R₅ or R₆ then the othersubstituent must be hydrogen;

R₃ and R₄ are hydrogen; and

R₁ and R₂ must be independently selected from the group consisting ofstraight or branched chain (C₁ -C₆)alkyl and (C₃ -C₇)cycloalkyl; or

R₁ and R₂ when taken together with the associated N(itrogen) atom isimidazole or may form a moiety as in formula II: ##STR4## wherein R₇,R₈, R₉ and R₁₀ must be hydrogen;

A must be carbon; and

m must be 0, 1.

with the proviso that:

if R₃, R₄, R₅ and R₆ are all hydrogen then R₁ and R₂ when taken togetherwith the associated N(itrogen) atom is imidazole or may form a moiety asin formula II: ##STR5## wherein R₇ and R₈ are as above defined but mustnot both be hydrogen;

R₉ and R₁₀ must be hydrogen;

A must be carbon; and

m must be 1;

and the pharmaceutically acceptable salts.

DESCRIPTION OF THE INVENTION

In the compounds of the invention, the groups and atoms are definedbelow:

(C₁ -C₆)alkyl group represent one to six carbon atoms either in astraight chain such as ethyl, n-butyl, n-hexyl or are branched such astert-butyl, 3-methylpentyl.

(C₁ -C₄)alkyl group represent one to four carbon atoms in a straightchain such as methylene, ethylene, propylene, butylene and are used totether a cycloalky, aryl, heterocycloalkyl or heteroaryl group to thecarbonyl moiety.

(C₁ -C₁₀)acyl group represent an alphatic part which may be straight orbranched chain saturated or may have carbon carbon unsaturation attachedto a carbonyl functionality and is exemplified by formyl, acetyl,propionyl, crotonyl, acryloyl groups.

(C₁ -C₁₀)alkoxy group represents an alphatic part which may be straightor branched chain, or may have carbon carbon unsaturation and isattached to an oxygen atom and is exemplified by methoxy and isobutoxy,sec-butoxy, isopropoxy, hexyloxy of which the (C₁ -C₄)alkoxy group arepreferred.

(C₃ -C₇)cycloalkyl group represents groups such as cyclopropyl,cyclopentyl, and cyclohexyl and these groups can be attached directly toa carbonyl moiety such as cycolpentylcarbonyl or to an interveningoxygen or nitrogen atom such as cyclohexyloxycarbonyl andcyclopentylaminocarbonyl respectively.

(C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl represents a three to seven carbon ringattached to a one to four carbon straight alkyl chain and is exemplifiedby cyclopropylmethyl, cyclohexylethyl and cyclobutylpropyl.

Heterocycloalkyl group represents a heterocyclic group having from fourto eight ring atoms, of which from 1 to 3 are heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur atoms with theremainder being carbon atoms. In the heterocyclic groups, the atomthrough which the heterocyclic is attached is preferably a carbon atom.Examples of such heterocyclic ring systems include tetrahydrofuran-3-yl,tetrahydropyran-4-yl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-piperidinyl,2-morpholinyl.

Aryl group represents an aromatic group such as phenyl, 2-naphthyl,4-biphenyl.

Heteroaryl group represents a heteroaromatic group having one or tworings with from five to ten ring atoms, of which one to four areheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur atoms with the remainder being carbon atoms. In the heterocyclicgroups the atom through which the heterocyclic is attached is preferablya carbon atom. Examples of such heteroaryl ring systems includepyrrolyl, thieyl, furyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl,quinolyl.

The aryl and heteroaryl ring systems may be unsubstituted or substitutedon the carbon atoms of the aryl or heteroaryl groups. Substituentsinclude (C₁ -C₆)alkyl, alkoxy, methylthio, dialkylamino, alkoxycarbonyl,dialkylaminocarbonyl, cyano, nitro, trifluoromethyl or halo selectedfrom fluoro, chloro, bromo and iodo.

The novel compounds of the present invention may be readily prepared inaccordance with one or more of the following reaction schemes whereinR_(1') and R_(2') are selected from (C₁ -C₆)alkyl or one of R_(1') andR_(2') is (C₁ -C₆)alkyl and the other is --(CH₂)_(n) R_(17') where n is2-6; or R_(1') and R_(2') when taken together with the associatedN(itrogen) form a moiety of formula II: ##STR6## where A' is C, N, O; mis 0, 1, or 2; R_(9') and R_(10') are selected from hydrogen,hydroxymethyl and (C₁ -C₆)trialkylsilyloxymethyl, with the proviso thatwhen m is 0 or 1 and one of the R_(7'), R_(8'), R_(9') and R₁₀ ' isother than hydrogen, the other substitutents are hydrogen and A' iscarbon;

R_(3'), R_(4'), R_(5'), R_(6'), R_(7'), R_(8'), and R_(17') areindependently selected from hydrogen, hydroxy, substituted hydroxy, (C₁-C₆)alkoxy and (C₁ -C₆)trialkylsilyloxy R₃ ' or R₄ ' may also beselected from (C₁ -C₆)alkyl; with the proviso that if there is asubstituent other than hydrogen at R_(5') or R_(6') the othersubstitutent must be hydrogen and R_(3') and R_(4') are hydrogen; withthe proviso that only one of R_(3') or R_(4') is (C₁ -C₆)alkyl, hydroxy,substituted hydroxy, (C₁ -C₆)alkoxy or (C₁ -C₆)trialkylsilyloxy; R₁₁ isisopropyl when R₁₂ is hydrogen or R₁₁ is phenyl when R₁₂ is methyl; R₁₃and R₁₄ are selected from hydrogen and (C₁ -C₆)alkyl; R₁₅ is hydrogen or(C₁ -C₆)alkyl; R₁₆ is hydrogen or (C₁ -C₆)alkyl; P is (C₁ -C₆)alkyl,aryl(C₁ -C₄)alkyl, substituted cycloalkyl or substituted oxazalone.##STR7##

SCHEME I

In accordance with Scheme I, the diamines of general formula 4 and 5 areprepared by a modification of previously described methods [U. Swenson,U. Hacksell, R. Dahlboom. Acta Pharm. Suec., (1978), 15, 67; H.Bittiger, J. Heid, U.S. Patent #3,354,178 (1967)]. The advantage, overthe published procedures, is the mild conditions used to remove thetrifluoroacetamide protecting group.

Propargylamine is treated with trifluoroacetic acid anhydride in asolvent such as diethyl ether, tetrahydrofuran or methylene chloride toafford trifluoroacetamide 2. Compound 2 is reacted withparaformaldehyde, acetic or propanoic acid, cuprous halide and asecondary amine such as pyrrolidine, dimethylamine, piperidine,(R)-3-acetoxypyrroldine or(S)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]methylpyrrolidine in aethereal solvent such as diethyl ether, tetrahydrofuran or dioxane atthe reflux temperature of the solvent to give the amine of generalformula 3. A compound of general formula 3 is reacted in an alcoholsolvent such as methanol, ethanol or isopropanol containing a mineralacid to produce a diamine of general formula 4. When compounds ofgeneral formula 3 contain an acid labile group, such as(S)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]methylpyrrolidine,treatment with sodium borohydride in an alcohol solvent gives diaminesof general formula 5. ##STR8##

SCHEME II

In accordance with Scheme II, ester 8, wherein R₁₅ =(C₁ -C₆)alkyl, isprepared by the procedure of J. K. Whitesell et al., J. Org. Chem.,1989,54,2258. Ester 8 wherein R₁₅ =hydrogen is prepared by the procedureof J. K. Whitesell et al., Tetrahedron, 1986, 42, 2993.

Phenylcyclohexanone, in the racemic or optically active form (Chima,1986, 40,318, Organic Synthesis, 1990, Vol 69, 1) is reacted with anα-ketoacid, such as pyruvic acid, in an inert solvent, such as benzeneor toluene, in the presence of a catalytic amount of p-toluenesulfonicacid. Water is removed by azeotropic distillation to give a compound ofgeneral formula 7 wherein R₁₅ =(C₁ -C₆)alkyl. A compound of formula 7 isreacted with allyltrimethylsilane in the presence of stannic chloride inan inert solvent, such as methylene chloride, at -78° C. to give acompound of general formula 8.

Compounds of general formula 13 are optically active, wherein one of R₁₃or R₁₄ =(C₁ -C₆)alkyl and the other one is hydrogen, are prepared by theprocedure of D. A. Evans et. al., J. Am. Chem. Soc.,1982, 104, 1737.

A compound of general formula 9 is reacted with a lower alkyllithiumreagent in an ether solvent, such as diethyl ether or tetrahydrofuran,at -78° C. followed by the addition of a (C₂ -C₈)alkylcarboxylic acidchloride to give compounds of general formula 10. Alternatively, acompound of the general formula 9 is reacted with a lower alkyllithiumreagent in an ether solvent, such as diethyl ether or tetrahydrofuran,at -78° C. followed by the addition of a 4-pentenoic acid chloride togive compounds of general formula 11. Reacting compounds of generalformula 10 with a lower alkyllithium reagent, such as n-butyllithium ort-butyllithium, in an inert solvent, such as diethyl ether ortetrahydrofuran, at -78° C.; followed by the addition of a 2-propenylhalide and warming to -20° C. gives products of general formula 12.Alternately, reacting compounds of general formula 11 with a loweralkyllithium reagent, such as n-butyl-lithium or t-butyllithium, in aninert solvent, such as diethyl ether or tetrahydrofuran, at -78° C.;followed by the addition of a (C₁ -C₆)alkyl halide and warming to -20°C. gives compounds of general formula 1.2. The addition of compounds ofgeneral formula 12 to a solution of a (C₁ -C₆)alkyl alcohol orphenylmethyl alcohol and an alkyllithium reagent in an ether solvent,such as diethyl ether or tetrahydrofuran, at 0° C. gives compounds ofgeneral formula 13.

Compounds of general formula 17, wherein R₁₆ =(C₁ -C₆)alkyl and theother is hydrogen, are prepared by the procedure of A. V. Rama Rao et.al., Tetrahedron Letters, 1988, 29, 2069.

The dialkyl ester of (C₁ -C₆)alkyl malonate 14 is treated, with analkali metal alkoxide and subsequently reacted with a 2-propenyl halide,such as allylbromide, to give the disubstituted malonate ester 15. Ester15 is subjected to saponification, using potassium hydroxide in a (C₁-C₆)alkyl alcohol, such as ethyl alcohol; followed by acidification,with a mineral acid; and decarboxylation by distillation to give theracemic acid 16. Reacting compound 15 with thionyl chloride or oxalylchloride; followed by the addition of a (C₁ -C₆)alkyl alcohol, such asethyl alcohol, or an arylmethyl alcohol, such as benzyl alcohol, givesthe racemic ester 17.

As cited in the reference, the racemic acid may be resolved by reactingthe product of treatment with thionyl chloride or oxalyl chloride with aresolving agent, such as L-phenylalaninol.

Compounds 8, 13 and 17 are of general formula 18, where P is aspreviously described. ##STR9##

SCHEME III

In accordance with Scheme III compounds of general formula 18 preparedin accordance with Scheme II are reacted with compounds of generalformulas 4, 5 prepared in accordance with Scheme I to ultimately yieldthe compounds of the present invention. Accordingly, compound of generalformula 18 is treated with a stream of ozone at -78° C. in methylenechloride or a (C₁ -C₆)alcohol, such as methyl alcohol or ethyl alcohol.The resulting solution is treated with a reducing agent, like athioether, such as dimethylsulfide, a phosphine, such astriphenylphosphine, or zinc and acetic acid, to obtain an aldehyde ofthe general formula 19. An aldehyde of general formula 19 is reactedwith a diamine of general formula 4 or 5 prepared as in Scheme I andsodium cyanoborohydride, in an alcohol solvent, such as methyl alcoholor ethyl alcohol containing a (C₁ -C₆)alkylcarboxylic acid or a strongmineral acid to maintain an acidic pH, to give an aminoester of generalformula 20. A compound of general formula 20 is converted to a lactam ofgeneral formula 21 by stirring at room temperature or heating at thereflux temperature of the alcohol solvent, such as methyl alcohol orethyl alcohol, in the presence of an alkalimetal carbonate.

A compound of general formula 21 wherein R_(3') or R_(4') is nothydroxyl, is reacted at room temperature with cyanogen bromide in anether solvent, such as diethyl ether, to give a compound of generalformula 22. When a compound of general formula 21 contains a freehydroxyl, (i.e., R₃ ' or R₄ '=hydroxyl), it is necessary to protect thehydroxyl group, for example as a silyl ether, by reacting the freehydroxyl with a trialkylsilyl chloride, such as t-butyldimethylsilylchloride, and a trialkylamine, such as triethylamine, in an inertsolvent, such as methylene chloride, before the compound is treated withcyanogen bromide. A compound of general formula 22 is treated with asecondary amine, such as pyrrolidine, dimethylamine, piperidine,(R)-3-acetoxypyrrolidine,(R)-[[(1,1-dimethylethyl)dimethylsilyl]oxy]pyrrolidine or(S)-2-[[[(1,1-dimethyethyl)dimethylsilyl]oxy]methy]pyrrolidine to give acompound of general formula 23, where the protecting groups areretained. Removal of the silyloxy protecting group is achieved bytreatment of the silylether with mineral acid or fluoride ion in analcohol solvent. A compound of general formula 21 can be converted to acompound of general formula 23 using the procedures described in U.S.Pat. No. 4,937,235 and in Schemes IV-IX of the present invention.##STR10##

SCHEME IV

In accordance with Scheme IV, the preparation of the compounds of thepresent invention wherein R₃ or R₄ are amino or azido are described. Inthe foregoing Scheme IV, Compound 24 is a subset of compound 23, whereR₃ ' and R₄ ' are independently selected from hydroxyl or R_(15')wherein R₁₅ is (C₁ -C₆)alkyl or hydrogen. Where R₁₅ is hydrogen, thecompounds may be prepared as in Schemes I-III or as described in U.S.Pat. No. 4,937,235. Where R₁₅ is (C₁ -C₆)alkyl, the compounds may beprepared as in Schemes I-III.

In accordance with Scheme IV, a compound of general formula 24 isreacted with an alkyl or arylsulfonyl chloride in the presence of anamine base such as pyridine or triethylamine; in an ether or achlorohydrocarbon solvent at 0° C. (±5° C.), to produce a compound ofgeneral formula 25. Treatment of compound 25 with an alkali metal azide,in an alcohol or a polar aprotic solvent such as dimethylformamide, atfrom room temperature to the reflux temperature of the solvent, gives acompound of general formula 26. Compound 26 is treated with a reducingagent, such as zinc in acetic acid or wet triphenylphosphine, to give acompound of general formula 27. ##STR11##

SCHEME V

In accordance with Scheme V, the preparation of the compounds of thepresent invention wherein R₅ or R₆ are amino or azido is described.Accordingly, a compound of general formula 28, prepared by the methodsdescribed in U.S. Pat. No. 4,937,235, is reacted with an alkyl orarylsulfonyl chloride in the presence of an amine base such as pyridineor triethylamine, in an ether or a chlorohydrocarbon solvent at 0° C.(±5° C.) to produce a compound of general formula 29. Treatment ofcompound 29 with an alkali metal azide, in an alcohol or a polar aproticsolvent such as dimethylformamide, at from room temperature to thereflux temperature of the solvent, gives a compound of general formula30. Compound 30 is treated with a reducing agent, such as zinc in aceticacid or wet triphenylphosphine, to give a compound of general formula31. ##STR12##

SCHEME VI

In accordance with Scheme VI, compound 24, prepared by methods describedin U.S. Pat. No. 4,937,235 or as in Schemes I-III, is reacted with acarboxylic acid chloride or anhydride such as (C₁ -C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, arylaryl(C₁ -C₄)alkyl, heteroaryl, substituted heteroaryl, or heteroaryl(C₁-C₄)alkyl in the presence of a base such as pyridine or triethylamine,in an ether or chlorohydrocarbon solvent, at 0° C. (±5° C.) to give acompound of general formula 32.

Compound 24 is reacted with a chloroformate such as a (C₁ -C₁₀)alkyl,(C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl,heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl(C₁-C₄)alkyl in the presence of a base such as pyridine or triethylamine,in an ether or chlorohydrocarbon solvent, at 0° C. (±5° C.) to give acompound of general formula 33.

Compound 24 is reacted with an isocyanate such as (C₁ -C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl,heteroaryl, or heteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as(C₁ -C₁₀)dialkyl, aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl orbis[aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine ortriethylamine, in an ether or chlorohydrocarbon solvent, at 0° C. (±5°C.) to give a compound of general Formula 34.

Alternatively, compound 35, prepared by the methods described in U.S.Pat. No. 4,937,235 is reacted with a carboxylic acid chloride oranhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁ -C₄)alkyl,heteroaryl, substituted heteroaryl, or heteroaryl(C₁ -C₄)alkyl in thepresence of a base such as pyridine or triethylamine, in an ether orchlorohydrocarbon solvent, at 0° C. (±5° C.) to give a compound ofgeneral formula 36.

Compound 35 is reacted with a chloroformate such as a (C₁ -C₁₀)alkyl,(C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl,heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl(C₁-C₄)alkyl in the presence of a base such as pyridine or triethylamine,in an ether or chlorohydrocarbon solvent, at 0° C. (±5° C.) to give acompound of general formula 37.

Compound 35 is reacted with an isocyanate such as (C₁ -C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl,heteroaryl, or heteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as(C₁ -C₁₀)dialkyl, aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl orbis[aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine ortriethylamine, in an ether or chlorohydrocarbon solvent, at 0° C. (±5°C.) to give a compound of general formula 38.

Compound 36, 37, and 38 are reacted with paraformaldehyde, acetic, acid,copper(I) or (II) chloride and a secondary amine as disclosed in R_(1')and R_(2') such as pyrrolidine, in an ether solvent, such as dioxane, inan inert atmosphere at the reflux temperature of the solvent, to give onbasification, the corresponding compound of general formula 32, 33, and34 wherein R₁ and R₂ are selected from R_(1') and R_(2'). ##STR13##

SCHEME VII

In accordance with Scheme VII, compound 39, prepared by the methodsdescribed in U.S. Pat. No. 4,937,235, is reacted with a carboxylic acidchloride or anhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁ -C₄)alkyl,heteroaryl, substituted heteroaryl, or heteroaryl(C₁ -C₄)alkyl in thepresence of a base such as pyridine or triethylamine, in an ether orchlorohydrocarbon solvent, at 0° C. (±5° C.) to give a compound ofgeneral formula 40.

Compound 39 is reacted with a with chloroformate such as a (C₁-C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl,heterocycloalkyl, heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁-C₄)alkyl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such aspyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at0° C. (±5° C.) to give a compound of general formula 41.

Compound 39 is reacted with an isocyanate such as (C₁ -C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl,heteroaryl, or heteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as(C₁ -C₁₀)dialkyl, aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl orbis[aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine ortriethylamine, in an ether or chlorohydrocarbon solvent, at 0° C. (±5°C.) to give a compound of general formula 42.

Alternatively, compound 43, prepared by the methods described in U.S.Pat. No. 4,937,235, is reacted with a carboxylic acid chloride oranhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁ -C₄)alkyl,heteroaryl, substituted heteroaryl, or heteroaryl(C₁ -C₄)alkyl in thepresence of a base such as pyridine or triethylamine, in an ether orchlorohydrocarbon solvent, at 0° C. (±5° C.) to give a compound ofgeneral formula 44.

Compound 43 is reacted with a chloroformate such as a (C₁ -C₁₀)alkyl,(C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl,heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl(C₁-C₄)alkyl in the presence of a base such as pyridine or triethylamine,in an ether or chlorohydrocarbon solvent, at 0° C. (±5° C.) to give acompound of general formula 45.

Compound 43 is reacted with an isocyanate such as (C₁ -C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl,heteroaryl, or heteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as(C₁ -C₁₀)dialkyl, aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl orbis[aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine ortriethylamine, in an ether or chlorohydrocarbon solvent, at 0° C. (±5°C.) to give a compound of general formula 46.

Compound 44, 45 and 46 are reacted with paraformaldehyde, acetic, acid,copper(I) or (II) chloride and a secondary amine as disclosed in R_(1')and R_(2') such as pyrrolidine, in an ether solvent, such as dioxane, inan inert atmosphere at the reflux temperature of the solvent, to give onbasification, the corresponding compound of general formula 40, 41, and42 wherein R₁ and R₂ are selected from R_(1') and R_(2'). ##STR14##

SCHEME VIII

In accordance with Scheme VIII, compounds of general formula 27,prepared in accordance with Scheme IV are reacted with a carboxylic acidchloride or anhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁ -C₄)alkyl,heteroaryl, substituted heteroaryl, or heteroayl(C₁ -C₄)alkyl in thepresence of a base such as pyridine or triethylamine, in an ether orchlorohydrocarbon solvent, at or near 0° C. to give a compound ofgeneral formula 47. The compounds of general formula 27 are prepared inaccordance with Scheme IV are reacted with a chloroformate such as a (C₁-C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇ )cycloalkyl(C₁ -C₄)alkyl,heterocycloalkyl, heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁-C₄)alkyl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such aspyridine or triethylamine, in an ether or chlorohydrocarbon solvent, ator near 0° C. to give a compound of general formula 48. ##STR15##

SCHEME IX

In accordance with Scheme IX, compound of general formula 49, preparedin accordance with U.S. Pat. No. 4,937,235 are reacted with a carboxylicacid chloride or anhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl,(C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁-C₄)alkyl, heteroaryl, substituted heteroaryl, or heteroaryl(C₁-C₄)alkyl in the presence of a base such as pyridine or triethylamine,in an ether or chlorohydrocarbon solvent, at or near 0° C. to give acompound of general formula 50. Compounds of general formula 49 arereacted with a chloroformate such as a (C₁ -C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl,heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl(C₁-C₄)alkyl in the presence of a base such as pyridine or triethylamine,in an ether or chlorohydrocarbon solvent, at or near 0° C. to give acompound of general formula 51. Compound of general formula 49 arereacted with an isocyanate such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl,(C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, heteroaryl, orheteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as (C₁-C₁₀)dialkyl, aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl orbis[aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine ortriethylamine, in an ether or chlorohydrocarbon solvent, at or near 0°C. to give a compound of general formula 52.

The compounds of this invention are tested for cholinergic activityaccording to the following procedures.

[³ H] Quinuclidinyl Benzilate Binding Assay

This assay is utilized in conjunction with the ³ H-Cis-methyldioxolanebinding assay to evaluate antagonist and high affinity agonist bindingproperties of CNS cholinergic agents. The procedure was adapted fromWatson, M., Yamamura, H. I., and Roeske, W. R., J. Pharmacol. Exp. Ther.237:411-418 (1986) and Watson, M., Roeske, W. R., and Yamamura, H. I.,J. Pharmacol. Exp. Ther. 237:419-427 (1986).

Tissue Preparation:

Rats are sacrificed by decapitation and the brain removed and placed onice. The cerebral cortex is dissected on a cold stage, weighed andhomogenized (Polytron, setting 5.5 with PT-10 saw-tooth generator for 15seconds) in 50 volumes (wet wt/vol) of ice-cold 10 mM (8.1 mM Na₂ HPO₄,1.9 mM KH₂ PO₄) sodium-potassium phosphate buffer (NaKPB), pH 7.4. Thehomogenate is placed in an ice bath for 30 seconds and homogenized againas above. This procedure is repeated once again for a total of threetimes. The resulting homogenate is then diluted 1:3000 (original wetwt/vol) with ice-cold NaKPB for use in the assay. The final proteincontent per 2.0 ml of incubation mixture is 0.1 mg.

Dilution of Compounds:

A stock solution of Atropine is prepared at 0.2 mM to definenon-specific binding (1 μM final conc). Test compounds are prepared at40 mM (final conc 1 mM) in buffer (if water soluble) or in absoluteethanol--1N HCl (1:1, v/v) and serially diluted to the desiredconcentrations. In general, dose-response profiles are examined between1 mM and 1 pM final concentrations.

Preparation of ³ H-QNB:

³ H-QNB (NEN, NET-656; specific activity=30.0 Ci/mmol) is diluted to 5nM, with NaPB (final concentration=0.25 nM activity 18,000 cpm at acounting efficiency of 55%).

³ H-QNB Binding Assay:

A typical protocol is outlined below:

    ______________________________________                                                                    Test                                              Tube         Buffer  Atropine                                                                             Compound                                                                              .sup.3 H-QNB                                                                         Tissue                             No.  ID*     μL   μL  μL   μL  ml                                 ______________________________________                                        1-2  Total   50      --     --      100    1.85                               3-4  NS      40      10     --      "      "                                  5-6  4e-11   --      --     50      "      "                                  7-8  4e-10   --      --     "       "      "                                   9-10                                                                              4e-09   --      --     "       "      "                                  11-12                                                                              4e-08   --      --     "       "      "                                  13-14                                                                              4e-07   --      --     "       "      "                                  15-16                                                                              4e-06   --      --     "       "      "                                  17-18                                                                              4e-05   --      --     "       "      "                                  19-20                                                                              4e-04   --      --     "       "      "                                  21-22                                                                              4e-03   --      --     "       "      "                                  23-24                                                                              4e-02   --      --     "       "      "                                  ______________________________________                                         *Stock concentration [M] of compound to be tested.                       

Components are added in the following order: test compound, radioligand,buffer or tissue to give a final volume of 2.0 ml. After adding thetissue homogenate, the tubes are thoroughly mixed and incubated at 25°C. for 120 minutes. At the end of 120 minutes, the samples are filteredthrough GF/B glass fiber filters (Whatman) using a 24 sample cellharvester (Brandel) under a vacuum of 15 mm Hg. The tubes are washedwith 5×3 ml ice-cold NaKPB. The filters are then placed in scintillationvials with 10 ml of scintillation cocktail (Beckman HP or HP/B), allowedto stand overnight, shaken and then counted. Specific binding iscalculated as Total--NS (non-specific). The percent inhibition ofspecific binding is then calculated and the Ki values computed usingeither the LIGAND or LUNDON software packages for competition binding.The results of this test on representative compounds of this inventionappear in Table I.

[³ H]-Cis-methyldioxolane Binding Assay (High Affinity)

This assay is utilized in conjunction with ³ H-QNB binding to evaluatehigh affinity agonist binding and antagonist properties of CNScholinergic agents. The procedure was adapted from Vickroy, T. W.,Roeske, W. R, and Yamamura, H. I, J. Pharmacol. Exp. Ther. 229:747-755(1984). This is a rapid filtration assay that is set up to label onlythe high affinity agonist conformation of the muscarinic cholinergicreceptor.

Tissue Preparation:

Rats are sacrificed by decapitation and the brain removed and placed onice. The cerebral cortex is dissected on a cold stage, weighed andhomogenized (Polytron, setting 5.5 with PT-10 saw-tooth generator for 15seconds) in 50 volumes (wet wt/vol) of ice-cold 10 mM (8.1 mM Na₂ HPO₄,1.9 mM KH₂ PO₄) sodium-potassium phosphate buffer (NaKPB), pH 7.4. Thehomogenate is placed in an ice bath for 30 seconds and homogenized againas above. This procedure is repeated once again for a total of threetimes. The resulting homogenate is then diluted 1:3000 (original wetwt/vol) with ice-cold NaKPB for use in the assay. The final proteincontent per 2.0 ml of incubation mixture is 0.1 mg.

Dilution of Compounds:

A stock solution of Atropine is prepared at 0.2 mM to definenon-specific binding (1 μM final conc). Test compounds are prepared at40 mM (final conc 1 mM) in buffer (if water soluble) or in absoluteethanol--1N HCl (1:1, v/v) and serially diluted to the desiredconcentrations. In general, dose-response profiles are examined between1 mM and 1 pM final concentrations.

Preparation of ³ H-CD:

³ H-CD (NEN, NET-647; specific activity=55.5 Ci/mmol) is diluted to 20nM with NaPB (final conc=1.0 nM, activity 75,000 cpm at a countingefficiency of 55%).

Technical Notes:

³ H-CD adheres readily to both glass and plastic surfaces. To eliminatethis problem (and the chance for introducing artifacts into theresults), stock vials, pipette tips and all glass tubes are routinelytreated with Prosil-28, a siliconizing agent, and oven dried prior touse in an assay. Additionally, the GF/B glass fiber filters arepre-soaked in an aqueous polyethylenimine (PEI) solution (0.1%, pH 7.0)prior to use.

All points in the inhibition curve (including total and non-specificbinding)are always measured on single PEI treated filter strips tominimize filter-to-filter variability. (See Bruns, R. F., et al. Anal.Biochem. 132:74-81 (1983) for the use of PEI treated filters infiltration receptor assays).

The ³ H-CD is prepared fresh in buffer just prior to use in the assay toavoid possible decomposition. It should be kept on an ice bath afterdilution in buffer.

³ H-CD Binding Assay:

A typical protocol is outlined below:

    ______________________________________                                                                    Test                                              Tube         Buffer  Atropine                                                                             Compound                                                                              .sup.3 H-QNB                                                                         Tissue                             No.  ID*     μL   μL  μL   μL  ml                                 ______________________________________                                        1-2  Total   50      --     --      100    1.85                               3-4  NS      40      10     --      "      "                                  5-6  4e-11   --      --     50      "      "                                  7-8  4e-10   --      --     "       "      "                                   9-10                                                                              4e-09   --      --     "       "      "                                  11-12                                                                              4e-08   --      --     "       "      "                                  13-14                                                                              4e-07   --      --     "       "      "                                  15-16                                                                              4e-06   --      --     "       "      "                                  17-18                                                                              4e-05   --      --     "       "      "                                  19-20                                                                              4e-04   --      --     "       "      "                                  21-22                                                                              4e-03   --      --     "       "      "                                  23-24                                                                              4e-02   --      --     "       "      "                                  ______________________________________                                         *Stock concentration [M] of compound to be tested.                       

Components are added in the following order: test compound, radioligand,buffer or tissue to give a final volume of 2.0 ml. After adding thetissue homogenate, the tubes are thoroughly mixed and incubated at 25°C. for 120 minutes. At the end of 120 minutes, the samples are filteredthrough GF/B glass fiber filters (Whatman) using a 24 sample cellharvester (Brandel) under a vacuum of 15 mm Hg. The tubes are washedwith 5×3 ml ice-cold NaKPB. The filters are then placed in scintillationvials with 10 ml of scintillation cocktail (Beckman HP or HP/B), allowedto stand overnight, shaken and then counted. Specific binding iscalculated as Total--NS (non-specific). The percent inhibition ofspecific binding is then calculated and the Ki values computed usingeither the LIGAND or LUNDON software packages for competition binding.The results of this test on representative compounds of this inventionappear in Table I.

                  TABLE 1                                                         ______________________________________                                        In vitro Binding Data                                                                                .sup.3 H-QNB                                                                           .sup.3 H-CD                                   Compound               Ki uM    Ki uM                                         ______________________________________                                        2,2,2-Trifluoro-N-[4(1-pyrrolidinyl)-2-                                                              18.5     8.88                                          butynyl]acetamide monohydrochloride                                           N-[4-Dimethylamino)-2-butynyl]-2,2,2-                                                                >100     6.10                                          trifluoroacetamide monohydrochloride                                          N-[(4-Diethylamino)-2-butynyl]-2,2,2-                                                                >100     4.07                                          trifluoroacetamide monohydrochloride                                          (S)-N-[4-[2-[[[(1,1-Dimethylethyl]-                                                                  >100     41.4                                          dimethylsilyl]oxy]methyl]-1-pyrro-                                            lidinyl]-2-butynyl]-2,2,2-trifluoro-                                          acetamide                                                                     4-(1-Pyrrolidinyl)-2-butyn-1-amine                                                                   >100     13.0                                          dihydrochloride                                                               N,N-Dimethyl-2-butyne-1,4-diamine                                                                    >100     20.5                                          dihydrochloride                                                               N,N-Diethyl-2-butyne-1,4-diamine                                                                     >100     >100                                          dihydrochloride                                                               Racemic-1-[4-Dimethylamino)-2-butynyl]-                                                              >100     >100                                          3-hydroxy-3-methyl-2-pyrrolidinone                                            Racemic-3-Hydroxy-3-methyl-1-[4-(1-pyrro-                                                            8.6      5.70                                          lidinyl)-2-butynyl]-2-pyrrolidinone                                           Racemic 1-[4-(1-Dimethylamino)-2-                                                                    21       0.41                                          butynyl]-3-methyl-2-pyrrolidinone                                             Racemic 1-[4-(1-Dimethylamino)-2-butynyl]-3-                                                         6.0      5.1                                           butynyl]-3-methyl-2-pyrrolidinone                                             (S)-1-[4-(1-Diethylamino)-2-                                                                         35.5     0.68                                          methyl-2-pyrrolidinone                                                        (R)-1-[4-(Dimethylamino)-2-butynyl]-3-                                                               7.7      0.073                                         methyl-2-pyrrolidinone                                                        Racemic 1-[4-(1H-imidazol-1-yl)-2-                                                                   6.7      0.057                                         butynyl]-3-methyl-2-pyrrolidinone                                             Racemic 1-[4-(1-azetidinyl)-2-butynyl-3-                                                             2.0      0.054                                         methyl-2-pyrrolidinone                                                        [R-[(R*,R* and R*,S*)]]-1-[4-[2-[[[(1,1-                                                             2.5      5.6                                           Dimethylethyl)dimethylsilyl]methyl]-1-                                        pyrrolidinyl]-2-butynyl]-3-methyl-2-                                          pyrrolidinone                                                                 [R-(R*,R* and R*, S*)]-1-[4-[3-[[(1,1-                                                               >100     >100                                          Dimethylethyl)dimethylsilyl]oxy]-1-                                           pyrrolidinyl]-2-butynyl]-3-methyl-2-                                          pyrrolidinone                                                                 (S)-1-[4-(Diethylamino)-2-butynyl]-3-                                                                7.6      15.4                                          [[(1,1-dimethylethyl)dimethylsilyl]-                                          oxy]-2-pyrrolidinone                                                          (S)-1-[4-(1-Azetidinyl)-2-butynyl]-3-                                                                5.8      5.6                                           [[(1,1-dimethylethyl)dimethylsilyl]-                                          oxy]-2-pyrrolidinone                                                          (R)-1-[4-(1-Azetidinyl)-2-butynyl]-3-                                                                >100     >100                                          [[(1,1-dimethylethyl)dimethylsilyl]-                                          oxy]-2-pyrrolidinone                                                          (S)-3-[[1,1-Dimethylethyl)dimethyl-                                                                  >100     24.3                                          silyl]oxy]-1-[4-(1H-imidazol-1-yl)-2-                                         butynyl-2-pyrrolidinone                                                       (R)-3-[[(1,1-Dimethylethyl)dimethyl-                                                                 >100     14.0                                          silyl]oxy]-1-[4-(1H-imidazol-1-yl)-2-                                         butynyl-2-pyrrolidinone                                                       (S)-3-Hydroxy-1-[4-(1H-imidazol-1-yl)-                                                               >100     0.12                                          2-butynyl]-2-pyrrolidinone                                                    1-[4-(1H-Imidazol-1-yl)-2-butynyl]-3-                                                                >100     2.0                                           hydroxy-2-pyrrolidinone                                                       (S)-1-[4-(Dimethylamino)-2-butynyl]-3-                                                               14.3     18.2                                          [[(1,1-Dimethylethyl)dimethylsilyl]-                                          oxy]-2-pyrrolidinone                                                          (S)-1-[4-(Dimethylamino)-2-butynyl]-3-                                                               26.9     0.043                                         hydroxy-2-pyrrolidinone                                                       (R)-1-[4-(Dimethylamino)-2-butynyl]-3-                                                               104.7    0.54                                          hydroxy-2-pyrrolidinone                                                       (S)-3-[[(1,1-Dimethylethyl)dimethyl-                                                                 2.7      3.0                                           silyl]oxy]-1-[4-(1-pyrrolidinyl)-2-                                           butynyl]-2-pyrrolidinone                                                      (S)-3-Hydroxy-1-[4-(1-pyrrolidinyl)-2-                                                               1.7      0.007                                         butynyl]-2-pyrrolidinone                                                      (R)-3-Hydroxy-1-[4-(1-pyrrolidinyl)-2-                                                               3.4      0.125                                         butynyl]-2-pyrrolidinone                                                      (S)-3-Hydroxy-1-[4-[(2-hydroxyethyl)-                                                                >100     1.82                                          methylamino]-2-butynyl]-2-pyrro-                                              lidinone                                                                      (R)-3-Hydroxy-1-[4-[(4-hydroxybutyl)-                                                                >100     1.45                                          methylamino]-2-butynyl]-2-pyrro-                                              lidinone                                                                      [R-(R*,S*)]-3-(Acetyloxy)-1-[4-[2-                                                                   500      1.7                                           [[[(1,1-dimethylethyl)dimethylsilyl]-                                         oxy]methyl]-1-pyrrolidinyl]-2-butynyl]-                                       2-pyrrolidinone                                                               [S-(R*,R*)]-3-(Acetyloxy)-1-[4-[2-                                                                   2.6      0.079                                         [[[(1,1-dimethylethyl)dimethylsilyl]-                                         oxy]methyl]-1-pyrrolidinyl]-2-                                                butynyl]-2-pyrrolidinone                                                      [S-(R*,S*)]-3-(Acetyloxy)-1-[4-[2-                                                                   >100     4.2                                           [[[(1,1-dimethylethyl)dimethylsilyl]-                                         oxy]methyl]-1-pyrrolidinyl]-2-                                                butynyl]-2-pyrrolidinone                                                      [R-(R*,R*)]-3-Acetyloxy)-1-[4-[2-                                                                    >100     10.1                                          [[[(1,1-dimethylethyl)dimethylsilyl]-                                         oxy]methyl]-1-pyrrolidinyl]-2-butynyl]-                                       2-pyrrolidinone                                                               (S)-3-(Acetyloxy)-1-[4-[2-(hydroxy-                                                                  >100     16.2                                          ethyl)methylamino]-2-butynyl]-2-                                              pyrrolidinone                                                                 (R)-3-(Acetyloxy)-1-[4-[2-(hydroxy-                                                                  >100     28.3                                          ethyl)methylamino]-2-butynyl]-2-pyrro-                                        lidinone                                                                      (S)-3-(Acetyloxy)-1-[4-[(4-hydroxy-                                                                  >100     8.21                                          butyl)methylamino]-2-butynyl]-2-pyrro-                                        lidinone                                                                      [R-(R*,S*)]-1-[4-[2-[[[(1,1-                                                                         0.5      0.47                                          Dimethylethyl)dimethylsilyl]oxy]-                                             methyl]-1-pyrrolidinyl]-2-butynyl]-                                           3-hydroxy-2-pyrrolidone                                                       [S-(R*,R*)]-1-[4-[2-[[[(1,1-                                                                         0.4      0.14                                          Dimethylethyl)dimethylsilyl]oxy]-                                             methyl]-1-pyrrolidinyl]-2-butynyl]-                                           3-hydroxy-2-pyrrolidinone                                                     [S-(R*,S*)]-1-[4-[2-[[[(1,1-Dimethyl-                                                                198      1.7                                           ethyl)dimethylsilyl]oxy]methyl]-1-                                            pyrrolidinyl]-2-butynyl]-3-hydroxy-                                           2-pyrrolidinone                                                               [R-(R*,R*)]-1-[4-[2-[[[(1,1-Dimethyl-                                                                >100     4.2                                           ethyl)dimethylsilyl]oxy]methyl]-1-                                            pyrrolidinyl]-2-butynyl]-3-hydroxy-2-                                         pyrrolidinone                                                                 (R)-3-Hydroxy-1-[4-[(2-hydroxyethyl)-                                                                >100     1.80                                          methylamino]-2-butynyl]-2-pyrro-                                              lidinone                                                                      (S)-3-Hydroxy-1-[4-[(4-hydroxybutyl)-                                                                >100     1.3                                           methylamino]-2-butynyl]-2-pyrro-                                              lidinone                                                                      [S-(R*,S*)]-3-Hydroxy-1-[4-[2-                                                                       >100     2.60                                          (hydroxymethyl)-1-pyrrolidinyl]-2-                                            butynyl]-2-pyrrolidinone                                                      [S-(R*,R*)]-3-Hydroxy-1-[4-[2-                                                                       >100     34.3                                          (hydroxymethyl)-1-pyrrolidinyl]-2-                                            butynyl]-2-pyrrolidinone                                                      (S)-3-(Methylthio)-1-[4-                                                                             53       1.04                                          (1-pyrrolidinyl)-2-butynyl]-2-                                                pyrrolidinone                                                                 (R)-3-(Methylithio)-1-[4-(1-pyrro-                                                                   3.6      1.4                                           lidinyl)-2-butynyl]-2-pyrroli-                                                dinone                                                                        (S)-1-[4-(Dimethylamino)-2-butynyl]-                                                                 >100     6.4                                           3-(methylthio)-2-pyrrolidinone                                                (R)-1-[4-(Dimethylamino)-2-butynyl]-                                                                 108      6.1                                           3-(methylthio)-2-pyrrolidinone                                                (S)-N,N,N-Trimethyl-4-[3-(methylthio)-                                                               1.8      0.31                                          2-oxo-1-pyrrolidinyl]-2-butyn-1-                                              aminium iodide                                                                (S)-3-Azido-1-[4-(1-pyrrolidinyl)-2-                                                                 3.14     0.16                                          butynyl]-2-pyrrolidinone                                                      (S)-3-Amino-1-[4-(1-pyrrolidinyl)-                                                                   73.6     0.41                                          2-butynyl]-2-pyrrolidinone dihydro-                                           chloride                                                                      (R)-3-Azido-1-[4-(1-pyrrolidinyl)-                                                                   28       0.21                                          2-butynyl]-2-pyrrolidinone                                                    (R)-3-Amino-1-[4-(1-pyrrolidinyl)-                                                                   6.1      0.35                                          2-butynyl]-2-pyrrolidinone dihydro-                                           chloride                                                                      (S)-3-Azido-1-[4-(dimethylamino)-                                                                    >100     0.63                                          2-butynyl]-2-pyrrolidinone                                                    (R)-3-Azido-1-[4-(dimethylamino)-                                                                    >100     0.50                                          2-butynyl]-2-pyrrolidinone                                                    (S)-4-(3-Azido-2-oxo-1-pyrro-                                                                        1.6      0.045                                         lidinyl)-N,N,N-trimethyl-2-butyn-                                             1-aminium iodide                                                              (R)-4-(3-Azido-2-oxo-1-pyrro-                                                                        0.8      0.039                                         lidinyl)-N,N,N-trimethyl-2-butyn-1-                                           aminium iodide                                                                (S)-3-Amino-1-[4-(dimethylamino)-                                                                    >100     2.6                                           2-butynyl]-2-pyrrolidinone dihydro-                                           chloride                                                                      (R)-3-Amino-1-[4-(dimethylamino)-2-                                                                  >100     0.89                                          butynyl]-2-pyrrolidinone dihydro-                                             chloride                                                                      (S)-2-Methylpropanoic acid 1-[4-                                                                     610      ND                                            (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                                            (S)-2,2-Dimethylpropanoic acid 1-                                                                    484      38.8                                          [4-(dimethylamino)-2-butynyl]-2-oxo-                                          3-pyrrolidinyl ester                                                          (S)-Decanoic acid 1-[4-(dimethyl-                                                                    0.6      0.023                                         amino)-2-butynyl]-2-oxo-3-pyrro-                                              lidinyl ester                                                                 (S)-Carbonic acid 1-[4-(dimethylamino)-                                                              10       0.306                                         2-butynyl]-2-oxo-3-pyrrolidinyl octyl                                         ester                                                                         (S)-Carbonic acid 1-[4-(dimethylamino)-                                                              15.1     2.16                                          2-butynyl]-2-oxo-3-pyrrolidinyl] methyl                                       ester                                                                         (S)-N,N,N-Trimethyl-4-[2-oxo-3-[(1-                                                                  0.003    0.156                                         oxodecyl)oxy]-1-pyrrolidinyl-2-butyn-                                         1-aminium iodide                                                              (S)-N,N,N-Trimethyl-4-[3-(2-methyl-1-                                                                64.3     6.96                                          oxopropoxy)-2-oxo-1-pyrrolidinyl]-2-                                          butyn-1-aminium iodide                                                        (S)-4-[3-(2,2-Dimethyl-1-oxopropoxy)-                                                                478      7.80                                          2-oxo-1-pyrrolidinyl]-N,N,N-trimethyl-                                        2-butyn-1-aminium iodide                                                      (S)-N,N,N-Trimethyl-4-[3-[[(octyloxy)-                                                               0.1      0.013                                         carbonyl]oxy]-2-oxo-1-pyrrolidinyl]-2-                                        butyn-1-aminium iodide                                                        (S)-2-Methylpropanoic acid 2-oxo-1-[4-                                                               7.2      0.162                                         (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                          lidinyl ester                                                                 (S)-2,2-Dimethylpropanoic acid 2-oxo-                                                                4.6      0.37                                          1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                           pyrrolidinyl ester                                                            (S)-3-[[(Methylamino)carbonyl]oxy-1-[4-                                                              433      >100                                          (1-pyrrolidinyl)-2-butynyl]-2-pyrro-                                          lidinone                                                                      (S)-Dimethylcarbamic acid 2-oxo-1-[4-                                                                40.3     9.56                                          (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                          lidinyl ester                                                                 (S)-Carbonic acid hexyl 2-oxo-1-[4-                                                                  1.7      0.015                                         (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                          lidinyl ester                                                                 (S)-Carbonic acid methyl                                                                             5.4      0.053                                         2-oxo-1-[4-(1-pyrrolidinyl)-2-buty-                                           nyl]-3-pyrrolidinyl ester                                                     (S)-Carbonic acid methyl 2-oxo-                                                                      10.4     0.23                                          1-[4-(1-pyrrolidinyl)-2-butynyl]-                                             3-pyrrolidinyl ester                                                          (R)-Propanoic acid 2-methyl-1-[4-                                                                    711      26.0                                          (dimethylamino)-2-butynyl]-2-oxo-                                             3-pyrrolidinyl ester                                                          (R)-2,2-Dimethylpropanoic acid                                                                       404      ND                                            1-[4-(dimethylamino)-2-butynyl]-2-                                            oxo-3-pyrrolidinyl ester                                                      (R)-Decanoic acid 1-[4-(dimethyl-                                                                    >100     0.73                                          amino)-2-butynyl]-2-oxo-3-pyrro-                                              lidinyl ester                                                                 (R)-Octylcarbamic acid 1-[4-(di-                                                                     32       1.43                                          methylamino)-2-butynyl]-2-oxo-3-                                              pyrrolidinyl ester                                                            (R)-Carbonic acid 1-[4-(dimethyl-                                                                    52       3.07                                          amino)-2-butynyl]-2-oxo-3-pyrro-                                              lidinyl methyl ester monohydro-                                               chloride                                                                      (R)-Carbonic acid 1-[4-(dimethyl-                                                                    1.5      1.04                                          amino)-2-butynyl]-2-oxo-3-pyrro-                                              lidinyl octy ester                                                            (R)-N,N,N-Trimethyl-4-[3-(2-methyl-                                                                  45       0.24                                          1-oxopropoxy)-2-oxo-1-pyrrolidinyl]-                                          2-butyn-1-aminium iodide                                                      (R)-4-[3-(2,2-Dimethyl-1-oxopropoxy)-                                                                >100     1.22                                          2-oxo-1-pyrrolidinyl]-N,N,N-trimethyl-                                        2-butyn-1-aminium iodide                                                      (R)-4-[2-Oxo-3-[(1-oxodecyl)oxy]-                                                                    0.2      0.050                                         1-pyrrolidinyl]-N,N,N-trimethyl-2-                                            butyn-1-aminium iodide                                                        (R)-N,N,N-Trimethyl-4-[3-[[(octyl-                                                                   0.5      0.49                                          amino)carbonyl]oxy]-2-oxo-1-pyrro-                                            lidinyl]-2-butyn-1-aminium iodide                                             (R)-N,N,N-Trimethyl-4-[3-[[(octyloxy)-                                                               0.2      0.010                                         carbonyl]oxy]-2-oxo-1-pyrrolidinyl]-                                          2-butyn-1-aminium iodide                                                      (R)-2-Methylpropanoic acid 2-oxo-1-                                                                  87       0.135                                         [4-(1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                       lidinyl ester                                                                 (R)-2,2-Dimethylpropanoic acid 2-oxo-                                                                10.2     0.50                                          1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                           pyrrolidinyl ester                                                            (R)-Decanoic acid 2-oxo-1-[4-(1-pyrro-                                                               0.2      0.097                                         lidinyl)2-butynyl]-3-pyrrolidinyl                                             ester                                                                         (R)-Carbonic acid 2-oxo-1-[4-(1-pyrro-                                                               1.4      0.11                                          lidinyl)-2-butynyl]-3-pyrrolidinyl                                            phenylmethyl ester                                                            (R)-Octylcarbamic acid 2-oxo-1-[4-(1-                                                                0.2      0.24                                          pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                       ester                                                                         (R)-Carbonic acid octyl 2-oxo-1-[4-                                                                  0.1      0.076                                         (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                          lidinyl ester                                                                 (R)-Carbonic acid methyl 2-oxo-1-[4-                                                                 27.3     0.35                                          (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                          lidinyl ester                                                                 (S)-Decanoic acid 2-oxo-1-[4-(1-pyrro-                                                               0.035    0.33                                          lidinyl)-2-butynyl]-4-pyrrolidinyl                                            ester                                                                         (S)-Carbonic acid methyl 2-oxo-1-[4-(1-                                                              1.8      0.85                                          pyrrolidiny)-2-butynyl]-4-pyrrolidinyl                                        ester                                                                         (S)-Octylcarbamic acid 2-oxo-1-[4-(1-                                                                0.13     0.35                                          pyrrolidinyl-2-butynyl]-4-pyrrolidinyl                                        ester                                                                         ______________________________________                                    

Those compounds which have ³ H-CD and ³ H-QNB Ki values of less than 100μM are considered active. The compounds tested can be divided into 3categories:

1. compounds which are products or therapeutic agents;

2. compounds which are a prodrug form of the products or therapeuticagents and 3. compounds which are reaction intermediates.

The term prodrug signifies a compound which is to some degree chemicallyand biochemically labile. When the prodrug is metabolized in the body,the active product or therapeutic agent is released or unmasked.

The pharmaceutical preparations of the present invention may contain,for example, from about 0.5% up to about 90% of the active ingredient incombination with the carrier, more usually between 5% and 60% by weight.

The effective dosage of active ingredient employed may vary with theparticular compound employed, the mode of administration, and theseverity of the condition being treated. In general, however,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.02 mg to about 100mg/kg of patient body weight, preferably given in divided doses two tofour times a day, or in sustained release form. For most patients, thetotal daily dosage is from about 1 mg to about 5,000 mg, preferably fromabout 1 mg to 20 mg. Dosage forms suitable for internal use comprisefrom about 0.25 to 5.0 mg of the active compound in intimate admixturewith a solid or liquid pharmaceutically acceptable carrier. This dosageregimen may be adjusted to provide the optimal therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation.

A decided practical advantage is that these active compounds may beadministered orally as well as by intravenous, intramuscular, orsubcutaneous routes if necessary. Solid carriers include starch,lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, andkaolin, while liquid carriers include sterile water, polyethyleneglycols, non-ionic surfactants, and edible oils such as corn, peanut,and sesame oils, as are appropriate to the nature of the activeingredient and the particular form of administration desired. Adjuvantscustomarily employed in the preparation of pharmaceutical compositionsmay be advantageously included, such as flavoring agents, coloringagents, and antioxidants, e.g., vitiamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exits. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water ethanol, polyol (e.g., glycerol, propylene glycol, and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

As used herein, "pharmaceutically acceptable carrier" includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in therapeuticcompositions is contemplated.

The use of the radioligand binding assays (³ H-QNB and ³ H-CD) tocharacterize the hydroxylated oxotremorine derivatives provides a usefulfirst approximation for the evaluation of the muscarinic agonist-likeprofile of a test compound. However, in using a prodrug methodology,intrinsic activity will not be observed until in vive hydrolysis ormetabolism to the active compound occurs. Therefore, radioligand bindingdata, performed on the carbonyl derivatives, will not provide leadinginformation. As a result, the observed overt effects after oraladministration to rats of the test carbonyl derivative, relative to itscorresponding hydroxylated oxotremorine compound, became the primary invivo pharmacological measure. These in vivo overt effects are attributedto the peripheral acetylcholine-like effects of the compound, such assalivation, tremor and diarrhea. The overt effects also provided dosinginformation for the behavioral tests of cognitive improvement.

The passive avoidance procedure (Olton, D.; Wenk, G. Phychopharmacology:The Third Generation of Progress, ed. Meltzer, H. Y. Raven Press, NewYork 1987; Rusted, H. H.; Warburton, D. H. Neuropsychobiology 1989, 21,31) is used as the primary behavioral model to measure potential memoryenhansing effect of the compound. The test performed in rats uses theantagonism of atropine-induced deficits (12 mg/kg s.c.) in retention ofa noxious consequence (foot shock). The behavioral test provides areasonably rapid assessment that, in conjuction with the evaluation ofside effects can serve as an initial basis for determining the likelypotential of these compounds for clinical efficacy.

In the atropine disruption of the passive avoidance procedure, rats areinjected s.c. with 12 mg/kg of atropine and placed into one side of atwo-compartment chamber. The side into which the rats are placed isbrightly illuminated. When the rat enters the darkened portion of theexperimental chamber a guillotine door separating the two compartmentsis lowered and the rat receives a 3-sec 0.75 mA electric shock. Ratsreceiving saline under this procedure do not enter the darkened portionof the chamber when tested 24 hours following this initial experience,whereas rats receiving atropine enter the chamber with a very brieflatency, similar to that obtained on the first exposure day. The testcompounds are evaluated for their ability to reverse the passiveavoidance deficits induced by atropine. For the atropine-reversalassessment, a range of doses of the test compounds is administered 50minutes prior to the atropine, which is administered 20 minutes beforethe initial experimental session. Doses of the test compounds aresuspended in methylcellulose and administered orally via a stainlesssteel feeding tube. The test session on day two is conducted withoutdrug administration and without shock. The rat is allowed 3 minutes toenter the darkened portion of the chamber at which time it is removed.The latency (sec) to enter the darkened chamber on the second test dayis the primary measure of the ability of the test compound to reverseatropine-induced deficits in the passive avoidance response. Compoundswhich produce a significant latency, when compared to the salinecontrols, are considered active.

In general, the carbonyl derivatives of the hydroxylated oxotremorinesare orally active in the passive avoidance procedure at doses that arelower than those which produce corresponding cholinergic side effects.In those compounds where activity in the passive avoidance procedure isnot noted, significant side effects are observed which are assumed tomask the desired pharmacological effect.

                  TABLE IB                                                        ______________________________________                                        in Vivo Pharmocological Data                                                                      Passive   Side Effect                                                         Avoidance Profile                                                             active    minimum                                                             dose or   effective                                                           range     dose (MED)                                                          (rat) po  (rat) po                                        Compound Name       μ mol/kg                                                                             μ mol/kg                                     ______________________________________                                        (S)-Butanoic acid 1-[4-       8.0                                             (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (S)-Hexanoic acid 1-[4-       5.9                                             (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (S)-Octanoic acid 1-[4-       8.0                                             (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (S)-Ethylcarbamic acid 1-[4-                                                                      13        >510                                            (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrroldinyl ester                                                       (S)-Butylcarbamic acid 1-[4-                                                                       12-100   >493                                            (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (S)-Hexylcarbamic acid 1-[4-  >510                                            (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (S)-Octylcarbamic acid 1-[4-                                                                      1-3       >520                                            (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (S)-1-[4-(Dimethylamino)-2-   2.2                                             butynyl]-2-oxo-3-pyrrolidinyl                                                 carbonic acid ethyl ester                                                     (S)-1-[4-(Dimethylamino)-2-                                                                       12-51     32                                              butynyl]-2-oxo-3-pyrrolidinyl                                                 carbonic acid butyl ester                                                     (S)-1-[4-(Dimethylamino)-2-                                                                       26        8                                               butynyl]-2-oxo-3-pyrrolidinyl                                                 carbonic acid hexyl ester                                                     (R)-Butanoic acid 1-[4-                                                                            13-105   127                                             (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (R)-Hexanoic acid 1-[4-                                                                           10-84     255                                             (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (R)-Octanoic acid 1-[4-                                                                           13        508                                             (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (R)-Ethylcarbamic acid 1-[4-  >510                                            (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (R)-Butylcarbamic acid 1-[4-                                                                      3-7       >340                                            (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      (R)-Hexylcarbamic acid 1-[4-                                                                       7-58     >530                                            (dimethylamino)-2-butynyl]-2-                                                 oxo-3-pyrrolidinyl ester                                                      R)-1-[4-(Dimethylamino-2-                                                                         110       258                                             butynyl]-2-oxo-3-pyrrolidinyl                                                 carbonic acid ethyl ester                                                     (R)-1-[4-(Dimethylamino)-2-                                                                       1.6, 3.1  127                                             butynyl]-2-oxo-3-pyrrolidinyl                                                 carbonic acid ethyl ester                                                     (R)-1-[4-(Dimethylamino)-2-                                                                        6, 46    254                                             butynyl]-2-oxo-3-pyrrolidinyl                                                 carbonic acid ethyl ester                                                     (S)-Butanoic acid 2-oxo-1-[4- 1.7                                             (1-pyrrolidinyl)-2-butynyl]-3-                                                pyrrolidinyl ester                                                            (S)-Hexanoic acid 2-oxo-1-[4- 1.8                                             (1-pyrrolidinyl)-2-butynyl]-3-                                                pyrrolidinyl ester                                                            (S)-Octanoic acid 1-[4-(1-    14                                              pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                                            (S)-Decanoic acid 2-oxo-1-[4-                                                                     6         14                                              (1-pyrrolidinyl)-2-butynyl]-3-                                                pyrrolidinyl ester                                                            (S)-Ethylcarbamic acid 2-oxo-                                                                     22-90     >490                                            1-[4-(1-pyrrolidinyl)-2-                                                      butynyl]-3-pyrrolidinyl ester                                                 (S)-Butylcarbamic acid 2-oxo-                                                                      22-180   225                                             [4-(1-pyrrolidinyl)-2-                                                        butynyl]-3-pyrrolidinyl ester                                                 (S)-Hexylcarbamic acid 2-oxo-                                                                     45        >450                                            1-[4-(1-pyrrolidinyl)-2-                                                      butynyl]-3-pyrrolidinyl ester                                                 (S)-Octylcarbamic acid 2-oxo-                                                                     11, 45    >450                                            1-[4-(1-pyrrolidinyl)-2-                                                      butynyl]-3-pyrrolidinyl ester                                                 (S)-2-Oxo-1-[4-(1-            1.7                                             pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl carbonic acid                                                    ethyl ester                                                                   (S)-2-Oxo-1-[4-(1-   1-10     0.9                                             pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl carbonic acid                                                    butyl ester                                                                   (S)-2-Oxo-1-[4-(1-            28                                              pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl carbonic acid                                                    octyl ester                                                                   (R)-Butanoic acid 2-oxo-1-[4-                                                                      5-18     7.2                                             (1-pyrrolidinyl)-2-butynyl]-3-                                                pyrrolidinyl ester                                                            (R)-Hexanoic acid 2-oxo-1-[4-                                                                     11, 22    7.0                                             (1-pyrrolidinyl)-2-butynyl]-3-                                                pyrrolidinyl ester                                                            (R)-Octanoic acid 2-oxo-1-[4-                                                                     2-5       14                                              (1-pyrrolidinyl)-2-butynyl]-3-                                                pyrrolidinyl ester                                                            (R)-Ethylcarbamic acid 2-oxo-                                                                     22        28                                              1-[4-(1-pyrrolidinyl)-2-                                                      butynyl]-3-pyrrolidinyl ester                                                 (R)-Butylcarbamic acid 2-oxo-                                                                     28        >243                                            1-[4-(1-pyrrolidinyl)-2-                                                      butynyl]-3-pyrrolidinyl ester                                                 (R)-Hexylcarbamic acid 2-oxo-                                                                     90        >450                                            1-[4-(1-pyrrolidinyl)-2-                                                      butynyl]-3-pyrrolidinyl ester                                                 (R)-2-Oxo-1-[4-(1-  14        14                                              pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl carbonic acid                                                    butyl ester                                                                   (R)-2-Oxo-1-[4-(1-  23        7                                               pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl carbonic acid                                                    hexyl ester                                                                   ______________________________________                                    

The following examples describe in detail the chemical synthesis ofrepresentative compounds of the present invention. The procedures areillustrations, and the invention should not be construed as beinglimited by chemical reactions and conditions they express. No attempthas been made to optimize the yields obtained in these reactions, and itwould be obvious to one skilled in the art that variations in reactiontimes, temperatures, solvents, and/or reagents could increase theyields.

EXAMPLE 1 2,2,2-Trifluoro-N-2-Propynylacetamide

To a stirring 0° C. solution of 15.0 g of propargylamine in 200 ml ofmethylene chloride is added, dropwise, a solution of 63.0 g oftrifluoroacetic anhydride in 50 ml of methylene chloride. The reactionis stirred at room temperature for 1 hour followed by the addition of100 ml of water. The mixture is washed with 150 ml of 1N hydrochloricacid and 150 ml of saturated sodium bicarbonate. The organic layer isdried, filtered and concentrated in vacuo. The residue is distilledunder vacuum (0.2 mm Hg) at 40° C. to give 32.1 g of the desired productas a colorless oil.

EXAMPLE 2 2,2,2-Trifluoro-N-[4-(1-Pyrrolidinyl)-2-Butynyl]AcetamideMonohydrochloride

A mixture of 50.0 g of product from Example 1, 47.1 g of pyrrolidine,24.9 g of paraformaldehyde, 50 ml of glacial acetic acid, 0.5 g ofcuprous chloride and 500 ml of dry dioxane is heated at refluxtemperature for 20 minutes. The reaction mixture is concentrated invacuo and made basic to pH 10-11 with concentrated ammonium hydroxide.The aqueous layer is extracted with methylene chloride. The combinedorganic extracts are dried over sodium sulfate, filtered through a padof diatomaceous earth and concentrated in vacuo. The residue isdistilled under vacuum (0.3 mm Hg) at 110°-120° C. to give the desiredproduct as a yellow oil. Eight grams of oil is dissolved in 1Nmethanolic hydrogen chloride. The resulting solid is collected andrecrystallized from methyl alcohol/diethyl ether to give 1.7 g of thedesired product as the monohydrochloride. MP 125°-127° C.

Following the general procedure of Example 2 and using2,2,2-trifluoro-N-2-propynylacetamide (Example 1), the products ofExamples 3-5, found in Table II, are prepared.

                                      TABLE II                                    __________________________________________________________________________                                MP °C.or [alpha].sub.D.sup.26              Example                                                                            Reactant  Product      (methylene chloride)                              __________________________________________________________________________    3    Dimethylamine                                                                           N-[4-Dimethylamino)-2-                                                                     112-114°                                                  butynyl]-2,2,2-trifluoro-                                                     acetamide monohydro-                                                          chloride                                                       4    Diethylamine                                                                            N-[4-(Diethylamino)-2-                                                                     111-112°                                                  butynyl]-2,2,2-trifluoro-                                                     acetamide monohydro-                                                          chloride                                                       5    (S)-2-[[[1,1-                                                                           (S)-N-[4-[2-[[[(1,1-                                                                       [alpha.sub.D.sup.26 = -41°                      (Dimethylethyl)-                                                                        Dimethylethyl]-                                                     dimethylsilyl]oxy-                                                                      dimethylsilyl]oxy]-                                                 methyl]-1-                                                                              methyl]-1-pyrrolidinyl]-                                            pyrrolidinyl]-2-                                                                        2-butynyl]-2,2,2-                                                   butynyl]-2,2,2-                                                                         trifluoroacetamide                                                  trifluoroacetamide                                                       __________________________________________________________________________

EXAMPLE 6 4-(1-Pyrrolidinyl)-2-Butyn-1-Amine Dihydrochloride

A mixture of 50.0 g of product from Example 2 and 267 ml of 4Nhydrochloric acid is heated at reflux temperature. After 2 hours, theprogress of the reaction is checked by thin layer chromatography, 70 mlof concentrated hydrochloric acid is added and the mixture is heated atreflux temperature overnight. The reaction is concentrated in vacuo andthe residue is washed with methylene chloride. The aqueous layer iscooled, made basic with 10N sodium hydroxide and extracted withmethylene chloride. The combined organic extracts are dried over sodiumsulfate, filtered and concentrated in vacuo to give 27.8 g of a darkoil. The oil is treated with 450 ml of 1N methanolic hydrogen chlorideand concentrated in vacuo. The resulting solid is recrystallized frommethyl alcohol/diethyl ether to give 31.2 g of the desired product asoff-white crystals. MP 192°-193° C.

Following the general procedure of Example 6, the products of Examples7-8, found in Table III, are prepared.

                                      TABLE III                                   __________________________________________________________________________         Starting                                                                 Example                                                                            Material                                                                            Reactant                                                                              Product     MP °C.                                  __________________________________________________________________________    7    Example 3                                                                           Hydrochloric                                                                          N,N-Dimethyl-2-butyne-                                                                    181-183°                                           acid    1,4-diamine                                                                   dihydrochloride                                            8    Example 4                                                                           Hydrochloric                                                                          N,N-Diethyl-2-butyne-                                                                     149-150°                                           acid    1,4-diamine                                                                   dihydrochloride                                            __________________________________________________________________________

EXAMPLE 9(S)-4-[2-[[[(1,1-Dimethylethyl)Dimethylsilyloxy]Methyl]-1-Pyrrolidinyl]-2-Butyn-1-Amine

To a stirring solution of 5.76 g of product from Example 5 in 145 ml oftetrahydrofuran and 3 ml of water is added 5.76 g of sodium borohydride.The reaction is stirred at room temperature for 18 hours followed byconcentration in vacuo to half volume. Saturated sodium chloride isadded and the mixture is extracted with methylene chloride. The organiclayer is concentrated in vacuo to give a viscous oil. The oil ispurified by chromatography (alumina, grade 2.5, 1% methylalcohol/methylene chloride) to give 1.92 g of the desired product as acolorless oil. [α]_(D) ²⁶ =-56° (methyl alcohol, c=1.016%).

EXAMPLE 10 Racemic1-[4-(Dimethylamino)-2-butynyl]-3-Hydroxy-3-Methyl-2-Pyrrolidinone

A solution of 5.0 g of 2-phenylcyclohexanol, 8.25 g of pyruvic acid, 0.3g of p-toluenesulfonic acid and 100 ml of toluene is heated at refluxtemperature. A Dean-Stark trap is used to collect the water distillate.The reaction is cooled, washed with aqueous sodium bicarbonate, driedand the filtrate concentrated in vacuo. The residue is purified bycolumn chromatography (silica gel, methylene chloride) to give 5.5 g oftrans-2-phenylcyclohexylpyruvate.

To a -78° C. solution of 15 g of trans-2-phenylcyclohexylpyruvate in 400ml of methylene chloride is added, dropwise via syringe, 9.0 g ofstannic chloride. The solution is stirred for 10 minutes followed by theaddition of 25 ml of allyltrimethylsilane in 15 ml of methylenechloride. The reaction is stirred at -78° C. for 1 hour. Eighteen ml oftriethylamine is added and the mixture allowed to warm to roomtemperature. Twenty-five ml of water and 10 g of diatomaceous earth isadded and the mixture filtered through a pad of diatomaceous earth. Theorganic layer is washed with water, dried and concentrated in vacuo. Theresidue is purified by chromatography (silica gel, 10% ethylacetate/petroleum ether) to give 16 g oftrans-2-phenylcyclohexyl-2-hydroxy-2-methyl-4-pentenoate.

A stream of ozone is passed through a solution of 5.0 g oftrans-2-phenylcyclohexyl-2-hydroxy-2-methyl-4-pentenoate in 150 ml ofmethylene chloride until a blue color persists. The blue color isdischarged with a stream of argon. Two ml of dimethylsulfide is addedand the solution allowed to warm to room temperature. The solution isconcentrated to approximately 75 ml, washed with saturated sodiumchloride, dried and concentrated in vacuo. The residue is diluted with100 ml of methyl alcohol and successively treated with 3.2 g of sodiumacetate, 10 ml of acetic acid and 3.0 g ofN,N-dimethyl-2-butyne-1,4-diamine hydrochloride. The resulting reactionmixture is stirred at room temperature for 10 minutes. One and one-halfgrams of sodium cyanoborohydride is added, in portions, over the next 2hours and the reaction is stirred overnight at room temperature. Themixture is concentrated in vacuo, partitioned between methylene chlorideand saturated aqueous sodium carbonate, and the layers separated. Theorganic layer is dried and concentrated in vacuo. The residue is amixture of the product and its ring open form4-[[4-(dimethylamino)-2-butynyl]amino]-2-methylbutanoic acid ethylester. The oil which is a mixture of the product and its ring open form,0.030 g of p-toluenesulfonic acid and 150 ml of ethyl alcohol is heatedat reflux temperature for 36 hours. The solution is concentrated invacuo and the residue purified by chromatography (alumina, 1-5% methylalcohol/methylene chloride) to give 1.4 g of the desired product as awaxy solid. MP 58°-59° C. CI-MS: m/z 211 (M+H⁺).

EXAMPLE 11 Racemic 3-Hydroxy-3-Methyl-1-[4-(1-Pyrrolidinyl)2-Butynyl]-2-Pyrrolidinone

The title compound is prepared by the procedure of Example 10 up to andincluding the ozonization procedure with the substitution of the productfrom Example 6 for the product of Example 7. CI-MS:m/z 237 (M+H⁺).

EXAMPLE 12 (S)-4-(1-Methylethyl)-3-(1-Oxo-4-Pentenyl)-2-Oxazolidinone

To a -78° C. solution of 5.0 g of 4-(1-methylethyl)-2-oxazolidinone in80 ml of tetrahydrofuran is added, dropwise, 15.5 ml of 2.5M n-butyllithium in hexane. After stirring for 30 minutes, a solution of 4.8 g of4-pentenyl chloride in 30 ml of tetrahydrofuran is added, dropwise, andthe resulting solution is stirred at -78° C. for 3.5 hours. The reactionis diluted with aqueous ammonium chloride and diethyl ether. The organiclayer is washed with water, dried and concentrated in vacuo. The residueis purified by chromatography (silica gel, 25% ethyl acetate/petroleumether) to give 5.8 g of the desired product as a pale yellow oil.[α]_(D) ²⁶ =+79° (methylene chloride).

EXAMPLE 13(4R-Cis)-5-Methyl-3-(1-Oxo-4-Pentenyl)-4-Phenyl-2-Oxazolidinone

The title compound is prepared by the procedure of Example 12, using 8.0g of (4R-cis)-5-methyl-3,4-phenyl-2-oxazolidinone, 18 ml of 2.5M n-butyllithium and 5.0 g of 4-pentenyl chloride to give 10.3 g of the desiredproduct as colorless crystals. MP 69°-70° C. [α]_(D) ²⁶ =+34° (methylenechloride)

EXAMPLE 14[S-(R*,R*)]-4-(1-Methylethyl)-3-(2-Methyl-1-Oxo-4-Pentenyl)-2-Oxazolidinone

To a -78° C. solution of 2.0 g of product from Example 12 in 40 ml oftetrahydrofuran is added, dropwise, 7.6 ml of 1.5M lithiumdiisopropylamide in tetrahydrofuran. The reaction is stirred at -78° C.for hour, 1.8 ml of iodomethane is added and the mixture stirred at -20°C. for 3 hours. The reaction is diluted with aqueous ammonium chlorideand methylene chloride. The organic layer is washed with water, driedand concentrated in vacuo. The residue is purified by chromatography(silica gel, 25% ethyl acetate/hexane) to give 1.3 g of the product ascolorless crystals. MP 54°-55° C. [α]_(D) ²⁶ =+108° (methylenechloride).

EXAMPLE 15 [4R-[3(R*), 4 Alpha,5alpha]]-5-Methyl-3-(2-Methyl-1-Oxo-4-Pentenyl)-4-Phenyl-2-Oxazolidinone

The title compound is prepared by the procedure of Example 14, using 4.0g of (4R-cis)-5-methyl-1-3-(-oxo-4-pentenyl)-4-phenyl-2-oxazolidinone,12.3 ml of 1.5M lithium diisopropylamide and 1.8 ml of iodomethane togive 2.9 g of the desired product as a pale yellow oil. [α]_(D) ²⁶ =-2°(methylene chloride)

EXAMPLE 16 (S)-2-Methyl-4-Pentenoic Acid Phenylmethyl Ester

To a 0° C. solution of 5.1 g of benzyl alcohol in 50 ml oftetrahydrofuran is added, dropwise, 3.8 ml of 2.5M n-butyl lithium inhexane. To this mixture is added, via cannula, a solution of 3.5 g ofS-(R*,R*)]4-(1-methylethyl)-3-(2-methyl-1-oxo-4-pentenyl)-2-oxazolidinonein 100 ml of tetrahydrofuran. The resulting solution is stirred at 0° C.for 2 hours. The reaction is diluted with saturated aqueous ammoniumchloride and methylene chloride. The organic layer is washed with water,dried and concentrated in vacuo. The residue is purified bychromatography (silica gel, methylene chloride) to give 2.9 g of thedesired product as a colorless oil. [α]_(D) ²⁶ =+3° (methylenechloride).

EXAMPLE 17 (R)-2-Methyl-4-Pentenoic Acid Phenylmethyl Ester

The title compound is prepared by the procedure of Example 16 using, 3.5g of [4R-[3(R*),4 alpha, 5alpha]]-5-methyl-3-(2-methyl-1-oxo-4-pentenyl)-4-phenyl-1-2-oxazolidinone,4.2 g of benzyl alcohol and 3.1 ml of 2.5M n-butyl lithium to give 2.4 gof the desired product as a colorless oil. [α]_(D) ²⁶ =-2° (methylenechloride).

EXAMPLE 18 Racemic 2-Methyl-4-Pentenoic Acid Phenylmethyl Ester

To 1.2 L of ethyl alcohol under an atmosphere of argon is added, inportions, 14.9 g of sodium. After all the sodium is dissolved, 103 ml ofdiethyl methylmalonate is added and the reaction is stirred at roomtemperature for 30 minutes. Fifty-one ml of allyl bromide is added,dropwise, and the resulting solution is stirred at room temperature for18 hours. The reaction is concentrated in vacuo and the residuepartitioned between water and methylene chloride. The organic layer isdried and concentrated in vacuo to give 77.7 g of methyl2-propenylpropane dicarboxylic acid diethyl ester.

A mixture of 77.7 g of methyl 2-propenylpropane dicarboxylic aciddiethyl ester, 123 g of potassium hydroxide and 625 ml of ethyl alcoholis heated at reflux for 53 hours. The reaction is cooled, concentratedin vacuo and the residue partitioned between water and diethyl ether.The aqueous layer is separated, made acidic with concentratedhydrochloric acid, saturated with solid sodium chloride and extractedwith diethyl ether. The combined diethyl ether layers are dried andconcentrated in vacuo to give 80 g of methyl 2-propenylpropanedicarboxylic acid as colorless crystals; MP 89°-90° C.

Twenty three grams of methyl 2-propenylpropane dicarboxylic acid isheated in a Kugelrohr apparatus at 170° C. (20 mm/Hg). Sixteen grams ofcolorless liquid is collected in an ice cooled receiver. Distillation ofthe liquid gave racemic 2-methyl-4-pentenoic acid as a colorless liquid;bp 115°-125° C., at 20 mm Hg.

To a solution of 25 g of racemic 2-methyl-4-pentenoic acid, 0.3 g ofdimethylformamide and 150 ml of methylene chloride is added, dropwise,48.2 ml of oxalyl chloride. The resulting solution is stirred at roomtemperature until gas evolution ceases (3 hours). The reaction isconcentrated in vacuo, diluted with methylene chloride andreconcentrated in vacuo to give 29.5 g of crude racemic2-methyl-4-pentenoyl chloride.

To a 0° C. solution of 23.8 g of benzyl alcohol, 0.05 g of4-(dimethylamino)pyridine, 18.3 g of pyridine and 250 ml of methylenechloride is added, dropwise, a solution of 29.5 g of racemic2-methyl-4-pentenoyl chloride in 50 ml of methylene chloride. Themixture is stirred at room temperature for 4 hours, followed bysuccessive washing with 2N hydrochloric acid, saturated sodiumbicarbonate and saturated sodium chloride. The organic layer is driedand concentrated in vacuo. The residue is purified by Kugelrohrdistillation to give 35.2 g of the desired product as a colorless oil;bp 70°-75° C. at 0.10 mm Hg.

EXAMPLE 19 Racemic1-[4-(1-Dimethylamino)-2-Butynyl]-3-Methyl-2-Pyrrolidinone

A stream of ozone is passed through a -78° C. solution of 1.0 g ofracemic 2-methyl-4-pentenoic acid phenylmethyl ester in 110 ml of methylalcohol until the blue color persists. The excess ozone is discharged bya stream of oxygen, followed by argon. One gram of zinc dust and 1.0 gof acetic acid is added and the resulting mixture allowed to warm toroom temperature; followed by stirring for 1 hour. The excess zinc isremoved by filtration and the filtrate is concentrated in vacuo. Theresidue is extracted with diethyl ether, filtered and the filtrateconcentrated in vacuo. The residue is purified by pad filtration (silicagel, 50% diethyl ether/petroleum ether) to give 1.01 g of racemic2-methyl-4-oxobutanoic acid phenylmethyl ester.

A solution of racemic 2-methyl-4-oxo-butanoic acid phenylmethyl ester in5 ml of methyl alcohol is added to a room temperature solution of 3.0 gof N,N-dimethyl-2-butyne-1,4-diamine dihydrochloride, 2.5 g of sodiumacetate and 30 ml of methyl alcohol. The resulting solution is stirredat room temperature for 15 minutes. One gram of sodium cyanoborohydrideis added, in portions, over 2 hours and the resulting mixture is stirredfor 18 hours. The reaction is made acidic with 1.0 ml of concentratedhydrochloric acid and concentrated in vacuo. The residue is made basicwith sodium hydroxide and extracted with methylene chloride. The organiclayer is washed with water, dried and concentrated in vacuo. The residueis purified by chromatography (alumina, activity grade 2.5, 25-100%ethyl acetate/petroleum ether) to give 5.7 g of the desired product as apale yellow oil. CI-MS:m/z 195 (M+H⁺).

Following the general procedure of Example 19, the products of Examples20-22, found in Table IV, are prepared.

                                      TABLE IV                                    __________________________________________________________________________                                 [alpha].sub.D.sup.26                                  Starting                (methylene chloride)                             Example                                                                            Material #                                                                          Reactant                                                                           Product      or CI-MS:m/z                                     __________________________________________________________________________    20   18    4    Racemic-1-[4-(1-                                                                           223 (M + H.sup.+)                                                Diethylamino)-2-butynl]-                                                      3-methyl-2-pyrrolidinone                                      21   16    3    (S)-1-[4-(Dimethylamino)-                                                                  -21°                                                      2-butynyl]-3-methyl-2-                                                        pyrrolidinone                                                 22   17    3    (R)-1-[4-(Dimethylamino)-                                                                  +22°                                                      2-butynyl]-3-methyl-2-                                                        pyrrolidinone                                                 __________________________________________________________________________

EXAMPLE 23(S)-1-(4-Bromo-2-Butynyl)-3-[[(1,1-Dimethylethyl)Dimethylsilyl]Oxy]-2-Pyrrolidinone

A mixture of 3.0 g of(S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2pyrrolidinone,0.9 g of paraformaldehyde, 2.5 ml of diethylamine, 3.5 ml of acetic acidand 0.050 g of cuprous chloride is stirred at room temperature for 15minutes, followed by heating at reflux temperature for 30 minutes. Thereaction is cooled, concentrated in vacuo, made basic (pH 10) withammonium hydroxide and partitioned between methylene chloride and water.The layers are separated, the aqueous layer reextracted and themethylene chloride extracts are combined. The organic solution is driedand concentrated in vacuo with 100 ml of toluene as co-solvent. theresidue is purified by chromatography (alumina, activity grade 2.5, 1-5%methyl alcohol/methylene chloride) to give 3.0 g of(S)-1-[4-(diethylamino)-2-butynyl]-3-[[(1,1-dimethylethyl)dimethylsily]oxy]-2-pyrrolidinoneas a yellow oil. [α]_(D) ²⁶ =-56 (methylene chloride).

A solution of 2.4 g of(S)-1-[4-diethylamino-2-butynyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinoneand 0.8 g of cyanogen bromide in 40 ml of diethyl ether is stirred atroom temperature for 18 hours. The solution is washed with 30 ml of 1Nhydrochloric acid and saturated sodium bicarbonate, dried andconcentrated in vacuo. The residue is purified by chromatography (silicagel, methylene chloride) to give 2.0 g of the desired product as acolorless oil. [α]_(D) ²⁶ =-31° (methylene chloride).

The starting(S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2-pyrrolidinoneis prepared by the procedure described in U.S. Pat. No. 4,937,235.

EXAMPLE 24(R)-1-(4-Bromo-2-Butynyl)-3-[[(1,1-Dimethylethyl)Dimethylsilyl]Oxy]-2-Pyrrolidinone

The title compound is prepared by the procedure of Example 23 using 10.7g of(R)-3-[[(1,1dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2-pyrrolidine,8.7 ml of diethylamine, 3.2 g of paraformaldehyde, 0.10 g of cuprouschloride, 15 ml of acetic acid and 100 ml of dioxane. Ten grams of thediamine intermediate is treated with 3.5 g of cyanogen bromide in 150 mlof diethyl ether to give 2.05 g of the desired compound as a yellow oil.[α]_(D) ²⁶ =+26° (methylene chloride).

The starting(R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2-pyrrolidinoneis prepared by the procedure described in U.S. Pat. No. 4,937,235.

EXAMPLE 25 1-(4-Bromo-2-Butynyl-3-Methyl)-2-Pyrrolidine

To 31.0 g of N,N-diethyl-2-butyne-1,4-diamine dihydrochloride dissolvedin 150 ml of methyl alcohol is added 30 ml of acetic acid and 23.8 g ofsodium acetate. The resulting suspension is stirred at room temperaturefor 20 minutes. Ten grams of 2-methyl-4-oxo-butanoic acid phenylmethylester (intermediate in Example 19), is added and the mixture is stirredfor 15 minutes. Three grams of sodium cyanoborohydride is added inportions and the mixture is stirred at room temperature for 18 hours.

The reaction mixture is concentrated in vacuo, made basic (pH 12) with5N sodium hydroxide and extracted with methylene chloride. The combinedorganic layers are dried, filtered and concentrated in vacuo to give 9.7g of oil. The oil is purified by chromatography (alumina, activity grade2.5, 0-75% ethyl acetate/petroleum ether) to give 5.9 g of1-[4-(diethylamino)-2-butynyl]-3-methyl-2-pyrrolidinone CI-MS:m/z 223(M+H).

A solution of 2.7 g of cyanogen bromide in 50 ml of diethyl ether isadded to 5.1 g of1-[4-(diethylamino)-2-butynyl]-3-methyl-2-pyrrolidinone dissolved in 50ml diethyl ether. The reaction is stirred at room temperature for 66hours. The mixture is washed with 1N hydrochloric acid and saturatedsodium bicarbonate, dried, filtered and concentrated in vacuo to give7.1 g of a light yellow oil. The oil is purified by chromatography(silica gel, petroleum ether/ethyl acetate) to give 3.8 g of the desiredproduct. CI-MS:m/z 247(M+NH₄ ⁺).

EXAMPLE 26(S)-3-[[(1,1-Dimethylethyl)Dimethylsilyl]Oxy]-1-[4-(1H-Imidazol-1-Yl)-2-Butynyl]-2-Pyrrolidinone

A solution of 2.0 g of(S)-1-(4-bromo-2-butynyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2pyrrolidinone,1.3 g of imidazole and 50 ml of tetrahydrofuran is stirred at roomtemperature for 72 hours. The solution is concentrated in vacuo. Theresidue is purified by chromatography (alumina, activity grade 2.5, 2%methyl alcohol/methylene chloride) to give 1.6 g of the desired productas a colorless oil. [α]_(D) ²⁶ =-30° (methylene chloride).

EXAMPLE 27(S)-3-Hydroxy-1-[4(1H-Imidazol-1-Yl)-2-Butynyl]-2-Pyrrolidinone

A solution of 1.6 g of1-(4-bromo-2-butynyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinonein 15 ml of 1N methanolic hydrogen chloride is stirred at roomtemperature for 2 hours. The reaction is concentrated in vacuo,partitioned between methylene chloride and saturated sodium carbonateand the layers are separated. The organic layer is dried andconcentrated in vacuo. The residue is purified by chromatography(alumina, activity grade 2.5, 2% methyl alcohol/methylene chloride) togive 0.9 g of the desired product as off-white crystals. MP 127°-128° C.[α]_(D) ²⁶ =-47°. (methylene chloride).

Following the general procedure of Examples 26 and 27, the products ofExamples 28-33 found in Table V are prepared.

                                      TABLE V                                     __________________________________________________________________________         Starting                 [alpha].sub.D.sup.26                            Example                                                                            Material #                                                                          Reactant                                                                            Product      (methylene chloride)                            __________________________________________________________________________    28   23    Azetidine                                                                           (S)-1-[4-(1-Azetidinyl)-                                                                   -34°                                                      2-butynyl]-3-[[(1,1-                                                          dimethylethyl)-                                                               dimethylsilyl]oxy]-2-                                                         pyrrolidinone                                                29   24    Imidazole                                                                           (R)-3-[[(1,1-                                                                              +32°                                                      Dimethylethyl)-                                                               dimethylsilyl]oxy]-1-                                                         [4-(1H-imidazol-1-yl)-2-                                                      butynyl]-2-pyrrolidinone                                     30   24    Azetidine                                                                           (R)-1-[4-(1-Azetidinyl)-2-                                                                 +36°                                                      butynyl]-3-[[(1,1-dimethyl-                                                   ethyl)dimethylsilyl]oxy]-2-                                                   pyrrolidinone                                                31   28    Methanolic                                                                          (S)-3-Hydroxy-1-[4-(1-                                                                     (not stable)                                               hydrogen                                                                            azetidinyl)-2-butynyl]-2-                                               chloride                                                                            pyrrolidinone                                                32   29    Methanolic                                                                          1-[4-(1H-Imidazol-1-yl)-2-                                                                 +39°                                                hydrogen                                                                            butynyl]-3-hydroxy-2-                                                   chloride                                                                            pyrrolidinone                                                33   30    Methanolic                                                                          (R)-3-Hydroxy-1-[4-(1-                                                                     (not stable)                                               hydrogen                                                                            azetidinyl)-2-butynyl]-                                                 chloride                                                                            2-pyrrolidinone                                              __________________________________________________________________________

Examples 34-49 (Table VI) are prepared according to the proceduresdescribed in U.S. Pat. No. 4,937,235. An alternate synthetic pathway tothe products in Examples 34-49 can be achieved using the processdescribed in Examples 23 and 24.

                                      TABLE VI                                    __________________________________________________________________________         Starting                      [alpha].sub.D.sup.26 or                    Example                                                                            Material #                                                                          Reactant                                                                              Product         CI-MS: m/z                                 __________________________________________________________________________    34   23    Dimethylamine                                                                         (S)-1-[4-(Dimethylamino)-                                                                     -37° (mc)                                              2-butynyl]-3-[[(1,1-                                                          dimethylethyl)-                                                               dimethylsilyl]oxy]-                                                           2-pyrrolidinone                                            35   24    Dimethylamine                                                                         (R)-1-[4-(Dimethylamino)-                                                                     ND                                                            2-butynyl]-3-[[(1,1-                                                          dimethylethyl)dimethyl-                                                       silyl]oxy]-2-pyrro-                                                           lidinone                                                   36   34    Methanolic                                                                            (S)-1-[4-(Dimethylamino)-2-                                                                   -71° (mc)                                      hydrogen                                                                              butynyl]-3-hydroxy-2-                                                 chloride                                                                              pyrrolidinone                                              37   35    Methanolic                                                                            (R)-1-[4-(Dimethylamino)-2-                                                                   +69° (mc)                                      hydrogen                                                                              butynyl-3-hydroxy-2-                                                  chloride                                                                              pyrrolidinone                                              38   23    Pyrrolidine                                                                           (S)-3-[[(1,1-Dimethylethyl)-                                                                  -35° (mc)                                              dimethylsilyl]oxy]-1-[4-(1-                                                   pyrrolidinyl)-2-butynyl]-2-                                                   pyrrolidinone                                              39   24    Pyrrolidine                                                                           (R)-3-[[(1,1-Dimethylethyl)-                                                                  ND                                                            dimethylsilyl]oxy]-1-[4-(1-                                                   pyrrolidinyl)-2-butynyl]-2-                                                   pyrrolidinone                                              40   23    Methanolic                                                                            (S)-3-Hydroxy-1-[4-                                                                           -63° (ma)                                      hydrogen                                                                              (1-pyrrolidinyl)-2-                                                   chloride                                                                              butynyl]-2-pyrrolidinone                                   41   24    Methanolic                                                                            (R)-3-Hydroxy-1-[4-                                                                           +60° (ma)                                      hydrogen                                                                              (1-pyrrolidinyl)-2-                                                   chloride                                                                              butynyl]-2-pyrrolidinone                                   42   23    Methyl- (S)-3-[[(1,1-Dimethylethyl)di-                                                                ND                                                    aminoethanol                                                                          methylsilyl]oxy]-1-[4-[(2-                                                                    (intermediate)                                                hydroxyethyl)methylamino]-2-                                                  butynyl]-2-pyrrolidinone                                   43   42    Methanolic                                                                            (S)-3-Hydroxy-1-[4-                                                                           -38° (ma)                                      hydrogen                                                                              [(2-hydroxyethyl)                                                     chloride                                                                              methylamino]-2-butynyl]-2-                                                    pyrrolidinone                                              44   24    Methylamino                                                                           (S)-3-[[(1,1-Dimethylethyl)di-                                                                ND                                                    butanol methylsilyl]oxy]-1-[4-[(4-                                                                    (intermediate)                                                hydroxybutyl)methylamino]-2-                                                  butynyl]-2-pyrrolidinone                                   45   44    Methanolic                                                                            (R)-3-Hydroxy-1-[4-                                                                           +33° (ma)                                      hydrogen                                                                              [(4-hydroxybutyl)methylamino]-                                        chloride                                                                              2-butynyl]-2-pyrrolidinone                                 46   25    Imidazole                                                                             Racemic 1-[4-(1H-imidazol-1-                                                                  218 (M + H.sup.+)                                             yl)-2-butynyl]-3-methyl-2-                                                    pyrrolidinone                                              47   25    Azetidine                                                                             Racemic 1-[4-(1-                                                                              207 (M + H.sup.+)                                             azetidinyl)-2-butynyl]-3-                                                     methyl-2-pyrrolidinone                                     48   25    (S)-3[[(1,1-                                                                          [R-[(R*,R* and R*,S*)]]-                                                                      365 (M + H.sup.+)                                     Dimethyl-                                                                             1-[4-[2-[[[(1,1-dimethyl-                                             ethyl)di-                                                                             ethyl)dimethysilyl]oxy]                                               methylsilyl]-                                                                         methyl]-1-pyrrolidinyl]-2-                                            oxy]methyl]-                                                                          butynyl]-3-methyl-2-pyrro-                                            1-pyrroli-                                                                            lidinone                                                              dinone                                                             49   25    (S)-3-[[(1,1-                                                                         [R-(R*,R* and R*,S*)]-1-                                                                      -2° (mc)                                       dimethylethyl)-                                                                       [4-[3[[(1,1-dimethylethyl)-                                                                   351 (M + H.sup.+)                                     dimethylsilyl]-                                                                       dimethylsilyl]oxy]-1-pyrro-                                           1-pyrrolidine                                                                         lidinyl-2-butynyl]-3-methyl-2-                                        carboxylic acid                                                                       pyrrolidinone                                                         phenyl methyl                                                                 ester                                                              __________________________________________________________________________     ND = Not done                                                                 (mc) = Rotation done in methylene chloride                                    (ma) = Rotation done in methyl alcohol                                   

methyl-1-pyrrolidine carboxylic acid phenyl methyl ester. Forty-five gof (R)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl esteris reacted with 38.4 g of (1,1-dimethylethyl)dimethylsilylchloride, 58ml of triethylamine, 1.3 g of 4-(dimethylamino)pyridine and 450 ml ofmethylene chloride to give 41.5 g of the desired product as a colorlessoil.

[α]_(D) ²⁶ +45° (methylene chloride).

EXAMPLE 52

(S)-3-(Acetoxy)-1-(2-propynyl)-2-pyrrolidinone

A solution of 4.3 g of (S)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone,10.6 ml of acetic anhydride, 0.6 ml of pyridine, 0.1 g of4-(dimethylamino)pyridine and 85 ml of methylene chloride is stirred atroom temperature for 18 hours. Twenty-five ml of methyl alcohol is addedand the reaction stirred for 20 minutes. The mixture is washed with 1Nhydrochloric acid and saturated sodium bicarbonate. The organic layer isdried, passed thorough a pad of hydrous magnesium silicate andconcentrated in vacuo to give 4.9 g of the desired product as a paleyellow oil.

[α]_(D) ²⁶ +60° (methylene chloride).

EXAMPLE 53

(R)-3-(Acetoxy)-1-(2-propynyl)-2-pyrrolidinone

The title compound is prepared by the procedure of Example 52 using 19.6g of (R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 26.6 ml of aceticanhydride, 17 ml of pyridine, 0.6 g of 4-(dimethylamino)pyridine and 200ml of methylene chloride to give 23.4 g of the desired product as a paleyellow oil.

[α]_(D) ²⁶ +59° (methylene chloride).

EXAMPLE 50

(S)-2-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinecarboxylicacid phenylmethyl ester

To a 0° C. solution of 25 g of (S)-2-pyrrolidinemethanol in 150 ml ofdiethyl ether is added 54.8 g of benzyl chloroformate. At mid point ofaddition, 49.4 ml of 5N sodium hydroxide is added, simultaneously, andthe reaction stirred at 0° C. for 2 hours. Diethyl ether is added, thelayers are separated and the aqueous layer reextracted with diethylether. The combined organic layers are dried, filtered and concentratedin vacuo. The residue is purified by chromatography (silica gel, 0-10%methyl alcohol/methylene chloride) to give 59.1 g of(S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester.

A solution 58.0 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acidphenylmethyl ester, 45.0 g of (1,1-dimethylethyl)dimethylsilylchloride,69 ml of triethylamine, 1.50 g of 4-(dimethylamino)pyridine and 450 mlof methylene chloride is stirred at room temperature for 18 hours. Theresulting solution is washed with water, 2N hydrochloric acid, saturatedsodium bicarbonate and sodium chloride. The organic layer is dried andconcentrated in vacuo. The residue, dissolved in methylene chloride, isfiltered through a silica gel pad and concentrated in vacuo to give 76.5g of the desired product as a colorless oil.

[α]_(D) ²⁶ -46° (methylene chloride).

EXAMPLE 51

(R)-2-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinecaboxylicacid phenylmethyl ester

The title compound is prepared by the procedure of Example 50 using 20.0g of (R)-2-pyrrolidinemethanol, 44.0 g of benzyl chloroformate and 200ml of diethyl ether to give 56.4 g of (R)-2-hydroxy

EXAMPLE 54

[R-(R*,S*)]-3-(Acetoxy)-1-[4-[2-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinyl]-2-butynyl]-pyrrolidinone

A mixture of 7.3 g of(S)-3[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinecarboxylic acid phenylmethyl ester, 0.40 g of 10% palladium on carbonand 225 ml of ethyl alcohol is hydrogenated in a Parr apparatus at roomtemperature under atmospheric pressure. The catalyst is removed byfiltration, the filtrate is diluted with 100 ml of toluene andconcentrated in vacuo. The residue is treated with 2.4 g of product fromExample 53, 0.65 g of paraformaldehyde, 0.38 g of cuprous chloride, 1.8ml of acetic acid and 75 ml of dioxane. The resulting mixture is heatedat reflux temperature for 45 minutes, cooled, made basic with ammoniumhydroxide and extracted with methylene chloride. The organic layer iswashed with water, dried and concentrated in vacuo. The residue ispurified by chromatography (alumina, activity grade 2.5, 1% methylalcohol/methylene chloride) to give 3.6 g of the desired product as anorange/red oil.

[α]_(D) ²⁶ =-4° (methyl alcohol).

Following the general procedure for Example 54, the products of Examples55-61, found in Table VII, are prepared.

                                      TABLE VII                                   __________________________________________________________________________         Starting                       [alpha].sub.D.sup.26                      Example                                                                            Material #                                                                          Reactant                                                                              Product          (methyl alcohol)                          __________________________________________________________________________    55   52    50      [S-(R*,R*)]-3-(Acetyloxy)-1-                                                                   -56°                                                  [4-[2-[[[(1,1-dimethylethyl)-                                                 dimethylsilyl]oxy]methyl]-                                                    1-pyrrolidinyl]-2-butynyl]-2-                                                 pyrrolidinone                                              56   52    51      [S-(R*,S*)]-3-(Acetyloxy)-1-                                                                    -4°                                                  [4-[2-[[[(1,1-dimethylethyl)                                                  dimethylsilyl]oxy]methyl]-                                                    1-pyrrolidinyl]-2-butynyl]-2-                                                 pyrrolidinone                                              57   53    51      [R-(R*,R*)]-3-Acetyloxy)-1-                                                                    +53°                                                  [4-[2-[[[(1,1-dimethylethyl)-                                                 dimethylsilyl]oxy]methyl]-                                                    1-pyrrolidinyl]-2-butynyl]-2-                                                 pyrrolidinone                                              58   52    2-      (S)-3-(Acetyloxy)-1-[4-[2-                                                                     -45°                                          (Methylamino)                                                                         (hydroxyethyl)methylamino]-2-                                         ethanol butynyl]-2-pyrrolidinone                                   59   53    2-      (R)-3-(Acetyloxy)-1-[4-[2-                                                                     +45°                                          (Methylamino)                                                                         (hydroxyethyl)methylamino]-2-                                         ethanol butynyl]-2-pyrrolidinone                                   60   52    2-      (S)-3-(Acetyloxy)-1-[4-[(4-hydroxy-                                                            -43°                                          (Methylamino)                                                                         butyl)methylamino]-2-butynyl]-2-                                      butanol pyrrolidinone                                              61   53    2-      (R)-3-(Acetyloxy)-1-[4-[(4-hydroxy-                                                            +43°                                          (Methylamino)                                                                         butyl)methylamino]-2-butynyl]-2-                                      butanol pyrrolidinone                                              __________________________________________________________________________

EXAMPLE 62

[R-(R*,S*)]-1-[4-[2-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinyl]-2-butynyl]-3-hydroxy-2-pyrrolidone

A solution of 0.90 g of product from Example 54, 1.4 g of potassiumcarbonate and 25 ml of methyl alcohol is stirred at room temperature for4 hours. The solution is passed through a pad of diatomaceous earth andthe filtrate concentrated in vacuo. The residue is purified bychromatography (alumina, activity grade 2.5, 10% methylalcohol/methylene chloride) to give 0.42 g of the desired product as ared/orange oil.

[α]_(D) ²⁶ =-15° (methyl alcohol).

Following the general procedure of Example 62, the products of Examples.63-69, found in Table VIII, are prepared.

                                      TABLE VIII                                  __________________________________________________________________________         Starting                       [alpha].sub.D.sup.26                      Example                                                                            Material #                                                                          Reactant                                                                              Product          (methyl alcohol)                          __________________________________________________________________________    63   55    Potassium                                                                             [S-(R*,R*)]-1-[4-[2-[[[(1,1-                                                                   -59°                                          carbonate                                                                             Dimethylethyl)dimethylsilyl]-                                                 oxy]methyl]-1-pyrrolidinyl]-                                                  2-butynyl]-3-hydroxy-2-                                                       pyrrolidinone                                              64   56    Potassium                                                                             [S-(R*,S*)]-1-[4-[2-[[[(1,1-                                                                    +7°                                          carbonate                                                                             Dimethylethyl)dimethylsilyl]-                                                 oxy]methyl]-1-pyrrolidinyl]-                                                  2-butynyl]-3-hydroxy-2-                                                       pyrrolidinone                                              65   57    Potassium                                                                             [R-(R*,R*)]-1-[4-[2-[[[(1,1-                                                                   +46°                                          carbonate                                                                             Dimethylethyl)dimethylsilyl]-                                                 oxy]methyl]-1-pyrrolidinyl]-                                                  2-butynyl]-3-hydroxy-2-                                                       pyrrolidinone                                              .sup. 66.sup.a                                                                     58    Potassium                                                                             (S)-3-Hydroxy-1-[4-[(2-hydroxy-                                                                -38°                                          carbonate                                                                             ethyl)methylamino]-2-butynyl]-2-                                              pyrrolidinone                                              67   59    Potassium                                                                             (R)-3-Hydroxy-1[4-[(2-hydroxy-                                                                 +36°                                          carbonate                                                                             ethyl)methylamino]-2-butynyl]-2-                                              pyrrolidinone                                              68   60    Potassium                                                                             (S)-3-Hydroxy-1-[4-[(4-                                                                        -35°                                          carbonate                                                                             hydroxybutyl)methylamino]-2-                                                  butynyl]-2-pyrrolidinone                                   .sup. 69.sup.b                                                                     61    Potassium                                                                             (R)-3-Hydroxy-1-[4-[(4-                                                                        +33°                                          carbonate                                                                             hydroxybutyl)methylamino]-2-                                                  butynyl]-2-pyrrolidinone                                   __________________________________________________________________________     .sup.a Same product as Example 43.                                            .sup.b Same product as Example 45.                                       

EXAMPLE 70

[S-(R*,S*)]-3-Hydroxy-1-[4-[2-(hydroxymethyl)-1-pyrrolidinyl]-2-butynyl]-2-pyrrolidinone

A solution of 1.62 g of product from Example 64, 35 ml of methyl alcoholand 2.1 ml of concentrated hydrochloric acid is stirred at roomtemperature for 4 hours. The solution is concentrated in vacuo and theresidue is partitioned between 10N sodium hydroxide and methylenechloride. The organic layer is dried and concentrated in vacuo. Theresidue is purified by pad filtration (alumina, 10% methylalcohol/methylene chloride) to give 0.910 g of the desired product as aviscous yellow oil.

[α]_(D) ²⁶ +2° (methyl alcohol).

Following the general procedure of Example 70, the products of Examples71 & 72, found in Table IX, are prepared.

                                      TABLE IX                                    __________________________________________________________________________         Starting                                                                 Example                                                                            Material #                                                                          Reactant                                                                             Product      [alpha].sub.D.sup.26                           __________________________________________________________________________    71   63    Hydrochloric                                                                         [S-(R*,R*)]-3-Hydroxy-1-                                                                   -73°                                               acid   [4-[2-(hydroxymethyl)-1-                                                                   (methyl alcohol)                                                 pyrrolidinyl]-2-butynyl]-2-                                                   pyrrolidinone                                               72   62    Hydrochloric                                                                         [R-(R*,S*)]-3-Hydroxy-1-                                                                   ND                                                        acid   [4-[2-(hydroxymethyl)-1-                                                      pyrrolidinyl]-2-butynyl]-2-                                                   pyrrolidinone                                               __________________________________________________________________________     ND = Not done                                                            

EXAMPLE 73

(S)-3-(Methylthio)-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone

A solution of 1.2 g of(S)-3-thio-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone in 100 ml ofmethylene chloride is added to a stirred suspension of 31 g of activatedsilica gel in 100 ml of methylene chloride. The mixture is stirred for15 minutes to ensure absorption of the thiol on the silica gel. Twohundred and twenty ml of 0.4M diethyl ether solution of diazomethane isadded in portions over 30 minutes. The solution is filtered and thesilica gel washed thoroughly with methyl alcohol. The filtrate isconcentrated in vacuo and the residue purified by chromatography(alumina, activity grade 2.5, 1% methyl alcohol/methylene chloride) togive 0.275 g of the desired product as a red/orange oil.

[α]_(D) ²⁶ =-49° (methyl alcohol).

Following the general procedure of Example 73, the products of Examples74-77, found in Table X, are prepared.

                                      TABLE X                                     __________________________________________________________________________         Starting                     [alpha].sub.D.sup.26                        Example                                                                            Material #                                                                            Reactant                                                                              Product      (methyl alcohol)                            __________________________________________________________________________    74   (R)-3-Thio-1-                                                                         Diazomethane                                                                          (R)-3-Methylthio)-1-[4-(1-                                                                 +40°                                      [4-(1-          pyrrolidinyl)-2-butynyl]-2-                                   pyrrolidinyl)-  pyrrolidinone                                                 2-butynyl-2-                                                                  pyrrolidinone                                                            75   (S)-3-Thio-1-                                                                         Diazomethane                                                                          (S)-1-[4-(Dimethylamino)-                                                                  -53°                                      [4-(1-dimethyl- 2-butynyl]-3-(methylthio)-                                    amino)-2-       2-pyrrolidinone                                               butynyl]-2-                                                                   pyrrolidinone                                                            76   (R)-3-Thio-1-                                                                         Diazomethane                                                                          (R)-1-[4-(Dimethylamino)-                                                                  +45°                                      [4-(1-dimethyl- 2-butynyl]-3-(methylthio)-                                    amino)-2-       2-pyrrolidinone                                               butynyl]-2-                                                                   pyrrolidinone                                                            77   75      Methyl  (S)-N,N,N-Trimethyl-4-[3-                                                                  +31°                                              iodide  (methylthio)-2-oxo-1-                                                         pyrrolidinyl]-2-butyn-1-                                                      aminium iodide                                           __________________________________________________________________________

EXAMPLE 78

(S)-3-Azido-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone

A solution of 0.75 ml of methanesulfonyl chloride in 5 ml of methylenechloride is added, dropwise, to a 0° C. solution of 1.0 g of productfrom Example 46, 1.5 ml of triethylamine and 25 ml of methylenechloride. The mixture is stirred at 0° C. for 11/2 hours. The reactionis diluted with methylene chloride and saturated sodium carbonate. Theorganic layer is washed with saturated sodium chloride, dried, dilutedwith toluene and concentrated in vacuo. The resulting 1.2 g of themethanesulfonate is used without further purification.

A solution of 1.2 g of the methanesulfonate, 1.4 g of sodium azide and25 ml of methyl alcohol is stirred at room temperature for 18 hours;followed by heating at reflux temperature for 1.5 hours. The reaction iscooled, diluted with diethyl ether and filtered through a pad ofdiatomaceous earth. The filtrate is concentrated in vacuo and theresidue partitioned between water and methylene chloride. The organiclayer is dried, concentrated in vacuo, and the residue is purified bychromatography (alumina, activity grade 2.5, 1% methyl alcohol/methylenechloride) to give 0.88 g of the desired product as a pale yellow oil.

[α]_(D) ²⁶ =-175°

EXAMPLE 79

(S)-3-Amino-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinonedihydrochloride

A mixture of 0.70 g of product from Example 78, 9.5 g of zinc dust and10 ml of acetic acid is stirred at room temperature for 1.5 hours. Thereaction is filtered, the zinc is washed with methylene chloride and thefiltrate concentrated in vacuo. The residue is partitioned betweenmethylene chloride and 6 ml of ammonium hydroxide. The organic layer isdried and concentrated in vacuo. The residue is dissolved in 1Nmethanolic hydrogen chloride and diluted with diethyl ether. Theresulting precipitate is collected and recrystallized from ethylalcohol/diethyl ether to give 0.24 g of the desired product as colorlesscrystals.

MP 224°-226° C.

[α]_(D) ²⁶ =-29° (methyl alcohol).

Following the general procedure of Example 79, the products of Examples80-87, found in Table XI, are prepared.

                                      TABLE XI                                    __________________________________________________________________________         Starting                    MP °C. or [alpha].sub.D.sup.26        Example                                                                            Material #                                                                              Reactant                                                                           Product      (methyl alcohol)                             __________________________________________________________________________    80   (R)-3-Hydroxy-1-                                                                        Sodium                                                                             (R)-3-Azido-1-[4-(1-                                                                       +190°                                      [4-(1-pyrrolidinyl)-                                                                    azide                                                                              pyrrolidinyl)-                                                 2-butynyl]-2-  2-butynyl]-2-                                                  pyrrolidinone  pyrrolidinone                                             81   (S)-3-Hydroxy-1-                                                                        Sodium                                                                             (S)-3-Azido-1-[4-                                                                          -188°                                      [4-(1-dimethyl-                                                                         azide                                                                              (dimethylamino)-2-                                             amino)-2-butynyl]-                                                                           butynyl]-2-pyrro-                                              2-pyrrolidinone                                                                              lidinone                                                  82   (R)-3-Hydroxy-1-                                                                        Sodium                                                                             (R)-3-Azido-1-[4-                                                                          +185°                                      [4-(1-dimethyl-                                                                         azide                                                                              (dimethylamino)-2-                                             amino)-2-butynyl]-                                                                           butynyl]-2-pyrro-                                              2-pyrrolidinone                                                                              lidinone                                                  83   81        Methyl                                                                             (S)-4-(3-Azido-2-oxo-                                                                      -122°                                                iodide                                                                             1-pyrrolidinyl)-N,N,                                                          N-trimethyl-2-butyn-1-                                                        aminium iodide                                            84   82        Methyl                                                                             (R)-4-(3-Azido-2-oxo-                                                                      +103°                                                iodide                                                                             1-pyrrolidinyl)-N,N,                                                          N-trimethyl-2-butyn-1-                                                        aminium iodide                                            85   80        Zinc/                                                                              (R)-3-Amino-1-[4-(1-                                                                        -30°                                                acetic                                                                             pyrrolidinyl)-2-                                                         acid butynyl]-2-pyrro-                                                             lidinone dihydro-                                                             chloride                                                  86   81        Zinc/                                                                              (S)-3-Amino-1-[4-                                                                           -33°                                                acetic                                                                             (dimethylamino)-2-                                                       acid butynyl]-2-pyrro-                                                             lidinone dihydro-                                                             chloride                                                  87   82        Zinc/                                                                              (R)-3-Amino-1-[4-                                                                           +32°                                                acetic                                                                             (dimethylamino)-2-                                                       acid butynyl]-2-pyrro-                                                             lidinone dihydro-                                                             chloride                                                  __________________________________________________________________________

EXAMPLE 88

(S)-2-Methylpropanoic acid1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester

A solution of 0.84 g of isobutyryl chloride in 15 ml of methylenechloride is added, dropwise, to a 0° C. solution of 1.4 g of(S)-3-hydroxy-1-[4-(1-dimethylamino)-2-butynyl]-2-pyrrolidinone, 3 ml oftriethylamine, 0.10 g of 4-(dimethylamino)pyridine and 25 ml methylenechloride. The mixture is stirred at room temperature for 18 hours. Twoml of methyl alcohol is added and the methylene chloride solution iswashed with 1N hydrochloric acid and saturated sodium carbonate, driedand concentrated in vacuo. The residue is purified by chromatography(alumina, activity grade 2.5, 1% methyl alcohol/methylene chloride) togive 1.65 g of the desired product as a pale yellow oil.

[α]_(D) ²⁶ =-44° (methylene chloride).

Following the general procedure of Example 88, the products of Examples89-124, found in Table XII, are prepared.

                                      TABLE XII                                   __________________________________________________________________________         Starting                       MP °C. or [alpha].sub.D.sup.26                                         3                                         Example                                                                            Material #                                                                            Reactant                                                                              Product        (methyl alcohol)                          __________________________________________________________________________    89   37      2,2-Dimethyl-                                                                         (S)-2,2-Dimethylpropanoic                                                                    -39°                                            propanoyl                                                                             acid 1-[4-(dimethylamino)-                                            chloride                                                                              2-butynyl]-2-oxo-3-pyrro-                                                     lidinyl ester                                            90   37      Decanoyl                                                                              (S)-Decanoic acid 1-[4-                                                                      -36°                                            chloride                                                                              (dimethylamino)-2-butynyl]-                                                   2-oxo-3-pyrrolidinyl ester                               91   37      Octyl   (S)-Carbonic acid 1-[4-                                                                      -40°                                            chloro- (dimethylamino)-2-butynyl]-                                           formate 2-oxo-3-pyrrolidinyl octyl ester                         92   37      Methyl  (S)-Carbonic acid 1-[4-                                                                      -60°                                            chloro- (dimethylamino)-2-butynyl]-                                           formate 2-oxo-3-pyrrolidinyl methyl                                                   ester                                                    93   90      Methyl  (S)-N,N,N-Trimethyl-4-[2-oxo-                                                                -28°                                            iodide  3-[(1-oxodecyl)oxy]-1-pyrro-                                                  lidinyl-2-butyn-1-aminium                                                     iodide                                                   94   88      Methyl  (S)-N,N,N-Trimethyl-4-[3-                                                                    -35°                                            iodide  (2-methyl-1-oxopropoxy)-                                                      2-oxo-1-pyrrolidinyl]-                                                        2-butyn-1-aminium iodide                                 95   89      Methyl  (S)-4-[3-(2,2-Dimethyl-1-                                                                    -33°                                            iodide  oxopropoxy)-2-oxo-1-pyrro-                                                    lidinyl]-N,N,N-trimethyl-                                                     2-butyn-1-aminium iodide                                 96   91      Methyl  (S)-N,N,N-Trimethyl-4-[3-                                                                    -33°                                            iodide  [[(octyloxy)carbonyol]oxy]-                                                   2-oxo-1-pyrrolidinyl]-                                                        2-butyn-1-aminium iodide                                 97   40      Isobutyryl                                                                            (S)-2-Methylpropanoic acid                                                                   -42°                                            chloride                                                                              2-oxo-1-[4-(1-pyrrolidinyl)-                                                  2-butynyl]-3-pyrrolidinyl                                                     ester                                                    98   40      Pivaloyl                                                                              (S)-2,2-Dimethylpropanoic                                                                    -37°                                            chloride                                                                              acid 2-oxo-1-[4-(1-pyrro-                                                     lidinyl)-2-butynyl]-3-                                                        pyrrolidinyl ester                                       99   40      Methyl  (S)-3-[[Methylamino)car-                                                                     -39°                                            isocyanate                                                                            bonyl]oxy]-1-[4-(1-pyrro-                                                     lidinyl)-2-butynyl]-2-                                                        pyrrolidinone                                            100  40      Dimethyl-                                                                             (S)-Dimethylcarbamic acid                                                                    -33°                                            carbamoyl                                                                             2-oxo-1-[4-(1-pyrrolidinyl)-                                          chloride                                                                              2-butynyl]-3-pyrrolidinyl                                                     ester                                                    101  40      Hexyl   (S)-Carbonic acid hexyl 2-                                                                   -43°                                            chloro- oxo-1-[4-(1-pyrrolidinyl)-                                            formate 2-butynyl]-3-pyrrolidinyl                                                     ester                                                    102  40      t-Butyl (S)-Carbonic acid 1,1-di-                                                                    -46°                                            chloro- methylethyl-2-oxo-1-[4-                                               formate (1-pyrrolidinyl)-2-butynyl]-                                                  3-pyrrolidinyl ester                                     103  40      Methyl  (S)-Carbonic acid methyl 2-                                                                  -56°                                            chloro- oxo-1-[4-(1-pyrrolidinyl)-2-                                          formate butynyl]-3-pyrrolidinyl ester                            104  36      Isobutyryl                                                                            (R)-Propanoic acid 2-                                                                        +44°                                            chloride                                                                              methyl-1-[4-(dimethyl-                                                        amino)-2-butynyl]-2-oxo-                                                      3-pyrrolidinyl ester                                     105  36      Pivaloyl                                                                              (R)-2,2-Dimethylpropanoic                                                                    +38°                                            chloride                                                                              acid 1-[4-(dimethylamino)-                                                    2-butynyl]-2-oxo-3-pyrro-                                                     lidinyl ester                                            106  36      Decanoyl                                                                              (R)-Decanoic acid 1-[4-                                                                      +35°                                            chloride                                                                              (dimethylamino)-2-butynyl]-                                                   2-oxo-3-pyrrolidinyl ester                               107  36      Decanoyl                                                                              (R)-Octylcarbamic acid 1-[4-                                                                 +28°                                            chloride                                                                              (dimethylamino)-2-butynyl]-                                                   2-oxo-3-pyrrolidinyl ester                               108  36      Methyl  (R)-Carbonic acid 1-[4-                                                                      +61°                                            chloro- (dimethylamino)-2-butynyl]-                                           formate 2-oxo-3-pyrrolidinyl methyl                                                   ester monohydrochloride                                  109  36      Octyl   (R)-Carbonic acid 1-[4-                                                                      +36°                                            chloro- (dimethylamino)-2-butynyl]-                                           formate 2-oxo-3-pyrrolidinyl octyl                                                    ester                                                    110  104     Methyl  (R)-N,N,N-Trimethyl-4-[3-(2-                                                                 +35°                                            iodide  methyl-1-oxopropoxy)-2-oxo-                                                                  MP 128-130°                                             1-pyrrolidinyl]-2-butyn-1                                                     aminium iodide                                           111  105     Methyl  (R)-4-[3-(2,2-Dimethyl-1-                                                                    +32°                                            iodide  oxopropoxy)-2-oxo-1-pyrro-                                                                   MP 160-162°                                             lidinyl]-N,N,N-trimethyl-                                                     2-butyn-1-aminium iodide                                 112  106     Methyl  (R)-4-[2-Oxo-3-[(1-oxodecyl)-                                                                +28°                                            iodide  oxy]-1-pyrrolidinyl]-N,N,N-                                                                  MP 103-105°                                             trimethyl-2-butyn-1-aminium                                                   iodide                                                   113  107     Methyl  (R)-N,N,N-Trimethyl-4-[3-                                                                    +34°                                            iodide  [[(octylamino)carbonyl]oxy]-                                                  2-oxo-1-pyrrolidinyl]-2-butyn-                                                1-aminium iodide                                         114  109     Methyl  (R)-N,N,N-Trimethyl-4-[2-                                                                    +34°                                            iodide  [[(octyloxy)carbonyl]oxy]-                                                    2-oxo-1-pyrrolidinyl]-2-                                                      butyn-1-aminium iodide                                   115  41      Isobutyryl                                                                            (R)-2-Methylpropanoic acid                                                                   +42°                                            chloride                                                                              2-oxo-1-[4-(1-pyrrolidinyl)-                                                  2-butynyl]-3-pyrrolidinyl                                                     ester                                                    116  41      Pivaloyl                                                                              (R)-2,2-Dimethylpropanoic                                                                    +37°                                            chloride                                                                              acid 2-oxo-1-[4-(1-pyrro-                                                     lidinyl)-2-butynyl]-3-                                                        pyrrolidinyl ester                                       117  41      Decanoyl                                                                              (R)-Decanoic acid 2-oxo-1-                                                                   +35°                                            chloride                                                                              [4-(1-pyrrolidinyl)-2-butynyl]-                                               3-pyrrolidinyl ester                                     118  41      Benzyl  (R)-Carbonic acid 2-oxo-1-                                                                   +38°                                            chloro- [4-(1-pyrrolidinyl)-2-                                                formate butynyl]-3-pyrrolidinyl                                                       phenylmethyl ester                                       119  41      Octyl   (R)-Octylcarbamic acid 2-                                                                    +28°                                            isocyanate                                                                            oxo-1-[4-(1-pyrrolidinyl)-                                                                   MP 47-49°                                               2-butynyl]-3-pyrrolidinyl                                                     ester                                                    120  41      Octyl   (R)-Carbonic acid octyl 2-                                                                   +39°                                            chloro- oxo-1-[4-(1-pyrrolidinyl)-2-                                          formate butynyl]-3-pyrrolidinyl ester                            121  41      Methyl  (R)-Carbonic acid methyl 2-                                                                  +56°                                            chloro- oxo-1-[4-(1-pyrrolidinyl)-2-                                          formate butynyl]-3-pyrrolidinyl ester                            122  (S)-4-Hydroxy-                                                                        Decanoyl                                                                              (S)-Decanoic acid 2-oxo-1-[4-                                                                -36°                                    1-[4-(1-                                                                              chloride                                                                              (1-pyrrolidinyl)-2-butynyl]-4-                                pyrrolidinyl)-  pyrrolidinyl ester                                            2-butynyl]-2-                                                                 pyrrolidinone                                                            123  (S)-4-Hydroxy-                                                                        Methyl  (S)-Carbonic acid methyl                                                                      -5°                                    1-[4-(1-pyrro-                                                                        chloro- 2-oxo-1-[4-(1-pyrro-                                          lidinyl)-2-                                                                           form-   lidinyl)-2-butynyl]-4-pyrro-                                  butynyl]-2-                                                                           ate     lidinyl ester                                                 pyrrolidinone                                                            124  (S)-4-Hydroxy                                                                         Octyl   (S)-Octylcarbamic acid                                                                        +6°                                    1-[4-(1-pyrro-                                                                        iso-    2-oxo-1-[4-(1-pyrrolidinyl)-                                  lidinyl)-2-                                                                           cyan-   2-butynyl]-4-pyrrolidinyl                                     butynyl-2-                                                                            ate     ester                                                         pyrrolidinone                                                            __________________________________________________________________________

Following the general procedure of Example 88, the Examples 125-Example163, found in Table XIII, are prepared.

                                      TABLE XIII                                  __________________________________________________________________________         Starting                            Optical                                   Material    Procedure               Rotation                             Example                                                                            Example     of                      [α].sub.25°.sup.D       No.  No.   Reagent                                                                             Example #                                                                           Name of Product   (MeOH)                               __________________________________________________________________________    125  36    Butyryl                                                                             88    (S)-Butanoic acid 1-[4-                                                                         -45°                                     chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     126  36    Hexanoyl                                                                            88    (S)-Hexanoic acid 1-[4-                                                                         -42°                                     chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     127  36    Octanoyl                                                                            88    (S)-Octanoic acid 1-[4-                                                                         -34°                                     chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     128  36    Ethyl 88    (S)-Ethylcarbamic acid 1-[4-                                                                    -35°                                     isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     129  36    Butyl 88    (S)-Butylcarbamic acid 1-[4-                                                                    -26°                                     isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     130  36    Hexyl 88    (S)-Hexylcarbamic acid 1-[4-                                                                    -31°                                     isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     131  36    Octyl 88    (S)-Octylcarbamic acid 1-[4-                                                                    -19°                                     isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     132  36    Ethyl 88    (S)-1-[4-(Dimethylamino)-2-butynyl]-                                                            -55°                                     chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                formate     ethyl ester                                            133  36    Butyl 88    (S)-1-[4-(Dimethylamino)-2-butynyl]-                                                            -52°                                     chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                formate     butyl ester                                            134  36    Hexyl 88    (S)-1-[4-(Dimethylamino)-2-butynyl]-                                                            -46°                                     chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                formate     hexyl ester                                            135  37    Butyrl                                                                              88    (R)-Butanoic acid 1-[4-                                                                         +47°                                     chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     136  37    Hexanoyl                                                                            88    (R)-Hexnoic acid 1-[4-                                                                          +41°                                     chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     137  37    Octanoyl                                                                            88    (R)-Octanoic acid 1-[4-                                                                         +40°                                     chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     138  37    Ethyl 88    (R)-Ethylcarbamic acid 1-[4-                                                                    +33°                                     isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     139  37    Butyl 88    (R)-Butylcarbamic acid 1-[4-                                                                    +36°                                     isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     140  37    Hexyl 88    (R)-Hexylcarbamic acid 1-[4-                                                                    +27°                                     isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                     141  37    Ethyl 88    (R)-1-[4-(Dimethylamino)-2-butynyl]-                                                            +57°                                     chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                formate     ethyl ester                                            142  37    Butyl 88    (R)-1-[4-(Dimethylamino)-2-butynyl]-                                                            +53°                                     Chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                formate     butyl ester                                            143  37    Hexyl 88    (R)-1-[4-(Dimethylamino)-2-butynyl]-                                                            +45°                                     chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                formate     hexyl ester                                            144  40    Butyryl                                                                             88    (S)-Butanoic acid 2-oxo-1-[4-(1-                                                                -43°                                     chloride    pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     145  40    Hexanoyl                                                                            88    (S)-Hexanoic acid 2-oxo-1-[4-(1-                                                                -39°                                     chloride    pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     146  40    Octanoyl                                                                            88    (S)-Octanoic acid 1-[4-(1-                                                                      -37°                                     chloride    pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     147  40    Decanoyl                                                                            88    (S)-Decanoic acid 2-oxo-1-[4-(1-                                                                -36°                                     chloride    pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     148  40    Ethyl 88    (S)-Ethylcarbamic acid 2-oxo-1-[4-(1-                                                           -30°                                     isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     149  40    Butyl 88    (S)-Butylcarbamic acid 1-2-oxo-[4-(1-                                                           -29°                                     isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     150  40    Hexyl 88    (S)-Hexylcarbamic acid 2-oxo-1-[4-(1-                                                           -26°                                     isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     151  40    Octyl 88    (S)-Octylcarbamic acid 2-oxo-1-[4-(1-                                                           -27°                                     isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     152  40    Ethyl 88    (S)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                              -52°                                     chloro-     butynyl]-3-pyrrolidinyl carbonic acid                             formate     ethyl ester                                            153  40    Butyl 88    (S)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                              -48°                                     chloro-     butynyl]-3-pyrrolidinyl carbonic acid                             formate     butyl ester                                            154  40    Octyl 88    (S)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                              -40°                                     chloro-     butynyl]-3-pyrrolidinyl carbonic acid                             formate     octyl ester                                            155  41    Butyryl                                                                             88    (R)-Butanoic acid 2-oxo-1-[4-(1-                                                                +40°                                     chloride    pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     156  41    Hexanoyl                                                                            88    (R)-Hexanoic acid 2-oxo-1-[4-(1-                                                                +41°                                     chloride    pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     157  41    Octanoyl                                                                            88    (R)-Octanoic acid 2-oxo-1-[4-(1-                                                                +40°                                     chloride    pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     158  41    Ethyl 88    (R)-Ethylcarbamic acid 2-oxo-1-[4-(1-                                                           +30°                                     isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     159  41    Butyl 88    (R)-Butylcarbamic acid 2-oxo-1-[4-(1-                                                           +27°                                     isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     160  41    Hexyl 88    (R)-Hexylcarbamic acid 2-oxo-1-[4-(1-                                                           +28°                                     isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl ester                                     161  41    Ethyl 88    (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                              +52°                                     chloro-     butynyl]-3-pyrrolidinyl carbonic acid                             formate     ethyl ester                                            162  41    Butyl 88    (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                              +45°                                     chloro-     butynyl]-3-pyrrolidinyl carbonic acid                             formate     butyl ester                                            163  41    Hexyl 88    (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                              +41°                                     chloro-     butynyl]-3-pyrrolidinyl carbonic acid                             formate     hexyl ester                                            __________________________________________________________________________

EXAMPLE 164

(R)-3-(Dimethylamino)-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone

Following the procedure of Example 78, a solution of 0.5 g of themethanesulfonate of the product from Example 40 and 0.5 g (excess)dimethylamine in 25 ml of methylene chloride is stirred at roomtemperature overnight. The reaction is concentrated at reduced pressureand the residue is purified by column chromatography (Al₂ O₃, ActivityGrade 2.5: methylene chloride to 1-5% (v/v) gradient methylenechloride/methanol) to give the product.

EXAMPLE 165

(S)-3-(Dimethylamino)-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone

A solution of 0.5 g of the product from Example 79 , 0.2 g ofparaformaldehyde (excess) and 1 ml of acetic acid in 10 ml of methanolis stirred at room temperature for 15 minutes. Portionwise, 0.5 g ofsodium cyanoborohydride, is added over 30 minutes. The resulting mixtureis stirred at room tempreature for 1 hour and concentrated at reducedpressure. The residue is basified with saturated aqueous sodiumcarbonate and extracted with methylene chloride. The methylene chloridesolution is dried over anhydrous sodium sulfate and concentrated atreduced pressure. The residue is purified by column chromatography (Al₂O₃, Activity Grade 2.5; methylene chloride to 1-5% (v/v) gradientmethylene chloride/methanol) to give the product.

EXAMPLE 166

(R) N-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl]acetamide

A solution of 0.2 g of acetyl chloride in 5 ml of methylene chloride isadded, dropwise, to a stirring 0° C. solution of 0.5 g of the productfrom Example 85 and 0.3 g of triethylamine in 10 ml of methylenechloride. The solution is allowed to warm to room temperature and isstirred overnight. The reaction is washed with saturated aqueous sodiumcarbonate, dried over anhydrous sodium sulfate and concentrated atreduced pressure to dryness. The residue is purified by columnchromatography (Al₂ O₃, Activity Grade 2.5: methylene chloride to 1-5%(v/v) gradient methylene chloride/methanol) to give the product.

EXAMPLE 167

Cyclopentanecarbonyl chloride

A solution of 1.0 g of oxalyl chloride in 15 ml of methylene chloride isadded, dropwise, to a 0° C. solution of 0.5 g of cyclopentane carboxylicacid in 15 ml of methylene chloride. The solution is allowed to warm toroom temperature and is stirred for 6 hours. The solution isconcentrated at reduced pressure, rediluted with 25 ml of methylenechloride and reconcentrated to give the corresponding acid chloride ofcyclopentane carboxylic acid.

EXAMPLE 168

(R)N-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl]cyclopentanecarboxamide

A solution of the product from Example 167 in 15 ml of methylenechloride is added, dropwise, to a 0° C. solution of 0.5 g of the productfrom Example 85 and 0.3 g of triethylamine in 10 ml of methylenechloride. The solution is allowed to warm to room temperature and isstirred overnight. The reaction is washed with saturated aqueous sodiumcarbonate, dried over anhydrous sodium sulfate and concentrated atreduced pressure to dryness. The residue is purified by columnchromatography (Al₂ O₃, Activity Grade 2.5: methylene chloride to 1-5%(v/v) gradient methylene chloride/methanol) to give the product.

The following Examples 169-184, found in Table XIV, are prepared in ananalogous manner.

In the following examples:

Reagent B, a carboxylic acid, is reacted by Procedure C, the resultingacid chloride intermediate is then reacted with the starting material Afollowing the procedure C' to give product D. For example, in Example169, cyclopentylacetic acid is reacted by the procedure of Example 167.The intermediate formed, cyclopentylcarbonyl chloride, is reacted withthe starting material from Example 41 using the procedure of Example 168to give the desired product.

                                      TABLE XIV                                   __________________________________________________________________________         Starting                                                                      Material      Procedure                                                  Example                                                                            Example                                                                             Reagent of Example                                                                          Name of Product                                      No.  No. (A)                                                                             (B)     (C) (C')                                                                            (D)                                                  __________________________________________________________________________    169  41    cyclopentyl-                                                                          167, 168                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                              acetic acid   butynyl]-3-pyrrolidinyl cyclopentyl-                                          acetamide                                            170  41    cyclohexyl-                                                                           167, 168                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                              acetic acid   butynyl]-3-pyrrolidinyl cyclohexyl-                                           acetamide                                            171  41    3-tetrahydro-                                                                         167, 168                                                                            Tetrahydro-N-[2-oxo-1-[4-(1-                                    furoic acid   pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl]-3-furancarboxamide                     172  40    [(S)-   167, 168                                                                            [S-(R*, R*)]-1-Methyl-N-[2-oxo-1-[4-(1-                         1-methyl-     pyrrolidinyl)-2-butynyl]-3-                                     pyroline]     pyrrolidinyl]-2-pyrrolidine-carboxamide              173  41    4-Cyano-                                                                              166   (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                              benzoyl       butynyl]-3-pyrrolidinyl-4-cyanobenzamide                        chloride                                                           174  41    2-Bromophenyl                                                                         167, 168                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                              acetic acid   butynyl]-3-pyrrolidinyl 2-bromophenyl-                                        acetamide                                            175  41    4-Methoxy-                                                                            167, 168                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                              phenyl acetic butynyl]-2-oxo-3-pyrrolidinyl 4-                                acid          methoxyphenyl-acetamide                              176  41    2-Furoyl                                                                              166   (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            chloride      butynyl]-3-pyrrolidinyl 2-furan-                                              carboxamide                                          177  41    nicotinyl                                                                             166   (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            chloride      butynyl]-3-pyrrolidinyl 3-pyridine-                                           carboxamide                                          178  41    isonicotinyl                                                                          166   (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            chloride      butynyl]-3-pyrrolidinyl 4-pyridine-                                           carboxamide                                          179  41    3-thiophene                                                                           167, 168                                                                            (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            carboxylic    butynyl]-3-pyrrolidinyl 3-thiophene-                            acid          carboxamide,                                         180  41    2-thiophene-                                                                          167, 168                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                              acetic acid   butynyl]-3-pyrrolidinyl 2-thiophene-                                          acetamide                                            181  41    3-thiophene-                                                                          167, 168                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                              acetic acid   butynyl]-3-pyrrolidinyl 3-thiophene-                                          acetamide                                            182  41    1-methyl-                                                                             167, 168                                                                            (R)-1-Methyl-N-[2-oxo-1-[4-(1-                                  imidazole-4-  pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                         acetic acid   1H-imidazole-4-carboxamide                           183  41    4-pyridine-                                                                           167, 168                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                              acetic acid   butynyl]-3-pyrrolidinyl 4-pyridine-                                           acetamide                                            184  41    3-pyridine-                                                                           167, 168                                                                            (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            acetic acid   butynyl]-3-pyrrolidinyl 3-pyridine-                                           acetamide                                            __________________________________________________________________________

EXAMPLE 185

Cyclopentyl chloroformate

A solution of 0.543 g of cyclopentyl alcohol in 15 ml of methylenechloride is added to a 0° C. solution of 1.0 ml of a 10% toluenesolution of phosgene in toluene in 10 ml of methylene chloride. Thereaction is allowed to warm to room temperature and is stirred for 3hours. The reaction is concentrated at reduced pressure, diluted with 15ml of toluene and reconcentrated to dryness to give the product.

EXAMPLE 186

(R) [2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl]carbamicacid, cyclopentylmethyl ester

Following the procedure of Example 168 and using the products fromExamples 85 and Example 185 the titled product is prepared.

The following Examples 187-198, found in Table XV, are prepared in ananalogous manner.

                                      TABLE XV                                    __________________________________________________________________________         Starting       Procedure                                                      Material       of                                                        Example                                                                            Example        Example                                                   No   No   Reagent   No    Name of Product                                     __________________________________________________________________________    187  41   cycloheptane                                                                            185, 186                                                                            (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                              methanol        butynyl]-3-pyrrolidinylcarbamic acid                                          cycloheptylmethyl ester                             188  41   cyclohexane                                                                             185, 186                                                                            (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                              methanol        butynyl]-3-pyrrolidinylcarbamic acid                                          cyclohexylmethyl ester                              189  41   tetrahydro-4H-                                                                          185, 186                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            pyran-4-ol      butynyl]-3-pyrrolidinylcarbamic acid                                          tetrahydro-2H-pyran-4-yl ester                      190  41   tetrahydro-3-                                                                           185, 186                                                                            2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                furanemethanol  butynyl]-3-pyrrolidinylcarbamic acid                                          (tetrahydro-3-furanyl)methyl ester                  191  41   4-methoxyphenyl                                                                         88, 91                                                                              (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                              chloroformate   butynyl]-3-pyrrolidinyl-carbamic acid                                         4-methoxyphenyl ester                               192  41   benzyl    88, 91                                                                              (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                              chloroformate   butynyl]-3-pyrrolidinylcarbamic acid                                          phenylmethyl ester                                  193  41   4-chlorobenzyl                                                                          88, 91                                                                              (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            chloroformate   butynyl]-3-pyrrolidinylcarbamic acid                                          (4-chlorophenyl)methyl ester                        194  41   2-        185, 186                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            thiophenemethanol                                                                             butynyl]-3-pyrrolidinylcarbamic acid                                          3-thienylmethyl ester                               195  41   2-(2-thienyl)                                                                           185, 186                                                                            (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                              ethanol         butynyl]-3-pyrrolidinyl carbamic acid                                         2-(2-thienyl)ethyl ester                            196  41   2-(3-thienyl)                                                                           185, 186                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            ethanol         butynyl]-3-pyrrolidinylcarbamic acid 2-                                       (3-thienyl)ethyl ester                              197  41   2-(2-pyridyl)                                                                           185, 186                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            ethanol         butynyl]-3-pyrrolidinylcarbamic acid                                          2-(2-pyridinyl)ethyl ester                          198  41   2-(6-methyl-2-                                                                          185, 186                                                                            (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                            pyridyl)ethanol butynyl]-3-pyrrolidinylcarbamic acid                                          2-(6-methyl-2-pyridinyl)ethyl                       __________________________________________________________________________                              ester                                           

EXAMPLE 199

(R)-1-(2-propynyl)-3-(methoxymethoxy)-2-pyrrolidinone

A solution of 1.0 g of chloromethyl methyl ether in 15 ml of methylenechloride is added dropwise to a solution of 1.5 g of(R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, prepared by the procedureof Example 1, U.S. Pat. No. 5,089,518, and 1.5 g ofethyldiisopropylamine in 15 ml of methylene chloride which is stirred inan ice bath. The reaction is allowed to warm to room temperature andstirred overnight. The solution was washed with water, aqueous sodiumbicarbonate and dried over anhydrous sodium sulfate. The methylenechloride solution is concentrated at reduced pressure and purified bycolumn chromatography (silica gel: mehylene chloride) to give theproduct.

EXAMPLE 200

(R)-1-[4-(Dimethylamino)-2-butynyl]-3-(methoxymethoxy)-2-pyrrolidinone

A solution of 2.2 g of product from Example 199, 0.93 g ofdimethylamine, 0.8 g of paraformaldehyde, 1.0 g of acetic acid, 0.050 gof cuprous chloride in 50 ml of dioxane is stirred at room temperaturefor two days. The mixture is cooled and concentrated at reducedpressure. The residue is basified with ammonium hydroxide and extractedwith methylene chloride. The methylene chloride solution is dried overanhydrous sodium sulfate, and concentrated at reduced pressure todryness. The residue is purified (Alumina, Activity Grade 2.5: ethylacetate/hexane 1:1 (v/v)) to give the product.

The following Examples 201-209, found in Table XVI, are prepared in ananalogous manner.

                                      TABLE XVI                                   __________________________________________________________________________         Starting                                                                      Material                                                                 Example                                                                            Example      Procedure of                                                No.  No.  Reagent Example #                                                                            Name of Product                                      __________________________________________________________________________    201  37   chloromethyl                                                                          199, 200                                                                             (R)-1-[4-(Dimethylamino)-2-butynyl]-                           ethyl ether    3-(ethoxymethoxy)-2-pyrrolidinone                    202  37   chloromethyl                                                                          199, 200                                                                             (R)-1-[4-(Dimethylamino)-2-butynyl]-                           isobutyl ether 3-[(2-methylpropoxy)methoxy]-2-                                               pyrrolidinone                                        203  37   chloromethyl                                                                          199, 200                                                                             (R)-3-(Butoxymethoxy)-1-[4-                                    butyl ether    (dimethylamino)-2-butynyl]-2-                                                 pyrrolidinone                                        204  37   chloromethyl                                                                          199, 200                                                                             (R)-1-[4-(Dimethylamino)-2-butynyl]-                           octyl ether    3-(octyloxymethoxy)-2-pyrrolidinone                  205  37   trimethylsilyl-                                                                       199, 200                                                                             (R)-1-[4-(Dimethylamino)-2-butynyl]-                           ethoxy methyl- 3-[[2-(trimethylsilyl)-                                        chloride       ethoxy]methoxy]-2-pyrrolidinone                      206  37   alpha, 4-                                                                             199, 200                                                                             (R)-1-[4-(Dimethylamino)-2-butynyl]-                           dichloroanisole                                                                              3-[(4-chlorophenoxy)methoxy]-2-                                               pyrrolidinone                                        207  37   benzyl chloro-                                                                        199, 200                                                                             (R)-1-[4-(1-Dimethylamino)-2-                                  methyl ether   butynyl]-3-[(phenylmethoxy)methoxy]-                                          2-pyrrolidinone                                      208  37   chloromethyl                                                                          199, 200                                                                             (R)-2,2-Dimethylpropanoic acid, [[1-                           pivalate       [4-(dimethylamino)-2-butynyl]-2-oxo-                                          3-pyrrolidinyl]oxy]methyl ester                      209  37   chloromethyl                                                                          199, 200                                                                             (R)-3-[(Benzoyloxy)methoxy]-1-[4-                              benzoate       (dimethylamino)-2-butynyl]-2-                                                 pyrrolidinone                                        __________________________________________________________________________

EXAMPLE 210

Cyclopentanecarbonyl chloride

A solution of 1.0 g of oxalylchloride in 15 ml of methylene chloride isadded dropwise to a 0° C. solution of 0.5 g of cyclopentane carboxylicacid in 15 ml of methylene chloride. The solution is allowed to warm toroom temperature and is stirred for 6 hours. The solution isconcentrated at reduced pressure, rediluted with 25 ml of methylenechloride and reconcentrated to give the product.

EXAMPLE 211

(S)-Cyclopentanecarboxylic acid2-oxo-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester

A solution of cyclopentanecarbonyl chloride from Example 210 in 15 ml ofmethylene chloride is added dropwise to a 0° C. solution of 0.5 g ofproduct from Example 85, 86 or 87 and 0.3 g of triethylamine in 10 ml ofmethylene chloride. The solution is allowed to warm to room temperatureand is stirred overnight. The reaction is washed with saturated aqueoussodium carbonate, dried over anhydrous sodium sulfate and concentratedat reduced pressure to dryness. The residue is purified by columnchromatography (Al₂ O₃, Activity Grade 2.5: methylene chloride to 1-5%(v/v) gradient methylene chloride/methanol) to give the product.

The following Examples 212-250, found in Table XVII, are prepared in ananalogous manner.

                                      TABLE XVII                                  __________________________________________________________________________                       Procedure                                                       Starting      of                                                         Example                                                                            Material      Example                                                    No.  No.  Reagent  No.   Name of Product                                      __________________________________________________________________________    212  40   cyclobutane                                                                            210, 211                                                                            (S)-Cyclobutanecarboxylic acid 2-oxo-1-                        carboxylic acid                                                                              [4-(1-pyrrolidinyl)-2-butynyl-3-                                              pyrrolidinyl ester                                   213  40   cyclopentane                                                                           210, 211                                                                            (S)-Cyclopentanecarboxylic acid 2-oxo-1-                       carboxylic acid                                                                              [4-(1-pyrrolidinyl)-2-butynyl]-3-                                             pyrrolidinyl ester                                   214  40   N-methyl-L-                                                                            210, 211                                                                            [(S) (R*,R*)]-1-Methyl-2-pyrrolidinyl-                         proline        carboxylic acid 2-oxo-1-[4-(1-                                                pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                       ester                                                215  40   3-       210, 211                                                                            (S)-3-tetrahydrofuroic acid 2-oxo-1-[4-                        tetrahydrofuroic                                                                             (1-pyrrolidinyl)-2-butynyl]-3-                                 acid           pyrrolidinyl ester                                   216  37   naphthoyl                                                                              88    (S)-Naphthoic acid 1-[4-(dimethylamino)-                       chloride       2-butynyl]-2-oxo-3-pyrrolidinyl ester                217  36   4-biphenyl                                                                             88    (S)-4-Biphenylcarboxylic acid 1-[4-                            carbonyl chloride                                                                            (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   218  36   benzoyl  88    (S)-Benzoic acid 1-[4-(dimethylamino)-2-                       chloride       butynyl]-2-oxo-3-pyrrolidinyl ester                  219  36   2-fluorobenzoyl                                                                        88    (S)-2-Flurobenzoic acid 1-[4-                                  chloride       (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   220  36   3-chlorobenzoyl                                                                        88    (S)-3-Chlorobenzoic acid 1-[4-                                 chloride       (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   221  36   4-bromobenzoyl                                                                         88    (S)-4-Bromobenzoic acid 1-[4-                                  chloride       (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   222  36   2-Iodobenzoyl                                                                          88    (S)-2-Iodobenzoic acid 1-[4-                                   chloride       (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   223  36   3-cyanobenzoyl                                                                         88    (S)-3-Cyanobenzoic acid 1-[4-                                  chloride       (diemthylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   224  36   4-nitrobenzoyl                                                                         88    (S)-4-Nitrobenzoic acid 1-[4-                                  chloride       (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   225  36   p-anisoyl                                                                              88    (S)-4-Methoxybenzoic acid 1-[4-                                chloride       (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   226  40   4-fluorophenyl                                                                         167, 88                                                                             (S)-4-Fluorophenylacetic acid 2-oxo-1-                         acetic acid    [4-(1-pyrrolidinyl)-2-butynyl]-3-                                             pyrrolidinyl ester                                   227  40   4-methoxyphenyl                                                                        167, 88                                                                             (S)-4-Methoxyphenylacetic acid 2-oxo-1-                        acetic acid    [4-(1-pyrrolidinyl)-2-butynyl]-3-                                             pyrrolidinyl ester                                   228  40   iso-nicotinoyl                                                                         88    (S)-3-Pyridinecarboxylic acid 2-oxo-1-                         chloride       [4-(1-pyrrolidinyl)-2-butynyl]-3-                                             pyrrolidinyl ester                                   229  40   2-furoyl chloride                                                                      88    (S)-2-Furancarboxylic acid 2-oxo-1-[4-                                        (1-pyrrolidiyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                   230  40   5-methyl-2-                                                                            210, 211                                                                            (S)-5-Methyl-2-pyrazinecarboxylic acid                         pyrazine       2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-                        carboxylic acid                                                                              3-pyrrolidinyl ester                                 231  40   nicotinoyl                                                                             88    (S)-3-Pyridinecarboxylic acid, 2-oxo-1-                        chloride       [4-(1-pyrrolidinyl)-2-butynyl]-3-                                             pyrrolidinyl ester                                   232  40   2-pyridylacetic                                                                        210, 211                                                                            (S)-2-Pyridylacetic acid 2-oxo-1-[4-(1-                        acid           pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                       ester                                                233  40   1-methyl-2-                                                                            210, 211                                                                            (S)-1-Methyl-1H-pyrrole-2-carboxylic                           pyrroleacetic  acid, 2-oxo-1-[4-(1-pyrrolidinyl)-2-                           acid           butynyl]-3-pyrrolidinyl ester                        234  40   2-thiopheneacetic                                                                      210, 211                                                                            (S)-2-Thiopheneacetic acid 2-oxo-1-[4-                         acid           (1-pyrrolidinyl)-2-butynyl]-3-                                                pyrrolidinyl ester                                   235  40   3-thiopheneacetic                                                                      210, 211                                                                            (S)-3-Thiopheneacetic acid 2-oxo-1-[4-                         acid           (1-pyrrolidinyl)-2-butynyl]-3-                                                pyrrolidinyl ester                                   236  40   1-methyl-                                                                              210, 211                                                                            (S)-1-Methyl-1H-imidazole-4-carboxylic                         imidazole-4-   acid, 2-oxo-1-[4-(1-pyrrolidinyl)-2-                           acetic acid    butynyl]-3-pyrrolidinyl ester                        237  40   4-pyridylacetic                                                                        210, 211                                                                            (S)-4-Pyridylacetic acid 2-oxo-1-[4-(1-                        acid           pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                       ester                                                238  40   3-pyridylacetic                                                                        210, 211                                                                            (S)-3-Pyridylacetic acid 2-oxo-1-[4-(1-                        acid           pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                       ester                                                239  40   butyryl chloride                                                                       88    (S)-Butanoic acid 2-oxo-1-[4-(1-                                              pyrrolidinyl-2-butynyl]-3-pyrrolidinyl                                        ester                                                240  37   cyclopentyl                                                                            88    (R)-Cyclopentylcarbonic acid 1-[4-                             chloroformate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   241  37   cyclohexyl                                                                             88    (R)-Cyclohexylcarbonic acid 1-[4-                              chloroformate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                   242  37   cyclopentane-                                                                          185, 88                                                                             (R) Cyclopentylmethylcarbonic acid, 1-                         methanol       [4-(dimethylamino)-2-butynyl]-2-oxo-3-                                        pyrrolidinyl ester                                   243  37   tetrahydro-4H-                                                                         185, 88                                                                             (R)-1-[4-(Dimethylamino)-2-butynyl]-2-                         pyran-4-ol     oxo-3-pyrrolidinylcarbonic acid,                                              tetrahydro-2H-pyran-4-yl ester                       244  37   tetrahydro-3-                                                                          185, 88                                                                             1-[4-(Dimethylamino)-2-butynyl]-2-oxo-3-                       furanemethanol pyrrolidinylcarbonic acid, (tetrahydro-                                       3-furanyl)methyl ester                               245  37   4-bromophenyl                                                                          88    (R)-4-Bromophenyl-1-[4-(dimethylamino)-                        chloroformate  2-butynyl]-2-oxo-3-pyrrolidinylcarbonic                                       acid ester                                           246  37   benzyl   88    (R)-1-[4-Dimethylamino)-2-butynyl]-2-                          chloroformate  oxo-3-pyrrolidinylcarbonic acid                                               phenylmethyl ester                                   247  37   2-thiophene                                                                            185, 88                                                                             (R)-1-[4-(Dimethylamino)-2-butynyl]-2-                         methanol       oxo-3-pyrrolidinylcarbonic acid,                                              2-thienylmethyl ester                                248  37   2-(2-thienyl)                                                                          185, 88                                                                             (R)-1-[4-(Dimethylamino)-2-butynyl]-2-                         ethanol        oxo-3-pyrrolidinylcarbonic acid, 2-(2-                                        thienyl)ethyl ester                                  249  37   2-(3-thienyl)                                                                          185, 88                                                                             (R)-1-[4-Dimethylamino)-2-butynyl]-2-                          ethanol        oxo-3-pyrrolidinylcarbonic acid, 2-(3-                                        thienyl)ethyl ester                                  250  36   2-(3-thienyl)                                                                          185, 88                                                                             (S)-1-[4-(Dimethylamino)-2-butynyl]-2-                         ethanol        oxo-3-pyrrolidinylcarbonic acid, 2-(3-                                        thienyl)ethyl ester                                  __________________________________________________________________________

The following Examples 251-252, found in Table XVIII, are prepared bythe procedure of Example 88 and 119.

                                      TABLE XVIII                                 __________________________________________________________________________                    Procedure                                                          Starting   of                                                            Example                                                                            Material   Example                                                       No.  No.  Reagent                                                                             No.   Name of Product                                         __________________________________________________________________________    251  36   cyclopentyl                                                                         88 19 (S)-Cyclopentylcarbamic acid 1-[4-                                isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                      252  36   cyclohexyl                                                                          88 119                                                                              (S)-Cyclohexylcarbamic acid 1-[4-                                 isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                      __________________________________________________________________________

EXAMPLE 253

3-Cyclopentylpropionyl chloride

A solution of 1.0 g of oxalyl chloride in 15 ml of methylene chloride isadded dropwise to a 0° C. solution of 0.65 g of 3-cyclopentylpropionicacid in 15 ml of methylene chloride. The solution is allowed to warm toroom temperature and is stirred for 6 hours. The solution isconcentrated at reduced pressure, rediluted with 25 ml of methylenechloride and reconcentrated to give 3-cyclopentylpropionyl chloride.

EXAMPLE 254

2-Cyclopentylethyl isocyanate

The procedure is an adaptation of procedure in Org. Syn. Col. Vol. II, p846, Col. Vol. VI, p 95. A solution of 0.65 g of 3-cyclopentylpropionylchloride (Example 253) in 10 ml of acetone is added dropwise to a 0° C.solution of 0.46 g of sodium azide in 5 ml of water When the addition iscomplete, stirring is continued for 1 hour. The mixture is extractedwith toluene, dried over anhydrous sodium sulfate and filtered. Thetoluene solution is added dropwise to 25 ml of toluene which is heatedat reflux temperature. When the addition is complete, the reaction isrefluxed until nitrogen evolution has ceased (ca 1 hour). The reactionis cooled and the resulting toluene solution of the correspondingisocyanate is then used as in Example 124, 119, 99, and all newexamples.

The following Examples 255-269, found in Table XIX, are prepared by theprocedure of Example 88 and 119.

                                      TABLE XIX                                   __________________________________________________________________________         Starting       Procedure                                                      Material       of                                                        Example                                                                            Example        Example                                                   No.  No.  Reagent   No.   Name of Product                                     __________________________________________________________________________    255  36   tetrahydro-3-                                                                           253, 254,                                                                           Tetrahydro-3-furanylcarbamic acid, 1-                         furoic acid                                                                             88    [4-dimethylamino)-2-butynyl]-2-oxo-3-                                         pyrrolidinyl ester                                  256  36   1-methyl-L-                                                                             253, 254,                                                                           [S-(R*,R*)] (1-Methyl-2-pyrrolidinyl)-                        pyroline  88    carbamic acid, 1-[4-(dimethylamino)-2-                                        butynyl]-2-oxo-3-pyrrolidinyl ester                 257  36   3-chlorophenyl                                                                          88    (S)-3-Chlorophenylcarbamic acid, 1-[4-                        isocyanate      (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                  258  36   benzyl isocyanate                                                                       88    (S)-Phenylmethylcarbamic acid, 1-[4-                                          (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                  259  36   phenethyl 88    (S)-(2-Phenylethyl)carbamic acid, 1-[4-                       isocyanate      (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                  260  36   3-thiophene                                                                             253, 254,                                                                           (S)-3-Thienylcarbamic acid, 1-[4-                             carboxylic acid                                                                         88    (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                  261  36   3-thiopheneacetic                                                                       253, 254,                                                                           (S)-3-Thienylmethylcarbamic acid 1-[4-                        acid      88    (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                  262  36   2-thiopheneacetic                                                                       253, 254,                                                                           (S)-2-Thienylmethylcarbamic acid 1-[4-                        acid      88    (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                  263  36   dimethyl  88    (S)-Dimethylcarbamic acid 1-[4-                               carbamoyl       (dimethylamino)-2-butynyl]-2-oxo-3-                           chloride        pyrrolidinyl ester                                  264  36   diethyl carbamoyl                                                                       88    (S)-Diethylcarbamic acid 1-[4-                                chloride        (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                  265  36   N-methyl-N-phenyl                                                                       88    (S)-N-Methyl-N-phenylcarbamic acid 1-[4-                      carbamoyl       (dimethylamino)-2-butynyl]-2-oxo-3-                           chloride        pyrrolidinyl ester                                  266  36   1-pyrrolidine                                                                           88    (S)-1-Pyrrolidinecarboxylic acid 1-[4-                        carbonyl chloride                                                                             (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                  267  36   4-morpholine                                                                            88    (S)-4-Morpholinecarboxylic acid 1-[4-                         carbonyl chloride                                                                             (dimethylamino)-2-butynyl]-2-oxo-3-                                           pyrrolidinyl ester                                  268  36   diphenyl  88    (S)-Diphenylcarbamic acid 1-[4-                               carbamoyl       (dimethylamino)-2-butynyl]-2-oxo-3-                           chloride        pyrrolidinyl ester                                  269  37   dibenzyl  88    (S)-Bis(phenylmethyl)carbamic acid 1-[4-                      carbamoyl       (dimethylamino)-2-butynyl]-2-oxo-3-                           chloride        pyrrolidinyl ester                                  __________________________________________________________________________

EXAMPLE 270

(S)-S-[1-[4-Dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl]-cyclopentylmethylthioicacid ester

A solution of product from Example 167 in 15 ml of methylene chloride isadded dropwise to a 0° C. solution of 0.5 g of product from Example 68,prepared according to U.S. Pat. No. 5,089,518, and 0.3 g oftriethylamine in 10 ml of methylene chloride. The solution is allowed towarm to room temperature and is stirred overnight. The reaction iswashed with saturated aqueous sodium carbonate, dried over anhydroussodium sulfate and concentrated at reduced pressure to dryness. Theresidue is purified by column chromatography (Al₂ O₃, Activity Grade2.5: methylene chloride to 1-5% (v/v) methylene chloride/methanol) togive the product.

The following Examples 271-299 found in Table XX, are prepared in ananalogous manner.

                                      TABLE XX                                    __________________________________________________________________________         Starting                                                                      Material       Procedure                                                 Example                                                                            Example        of Example                                                No.  No.  Reagent   No.   Name of Product                                     __________________________________________________________________________    271  41   cyclobutane                                                                             167, 270                                                                            (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         carboxylic acid butynyl]-3-pyrrolidinyl]                                                      cyclobutanecarbothioic acid ester                   272  41   cyclopentane                                                                            167, 270                                                                            (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         carboxylic acid butynyl]-3-pyrrolidinyl]                                                      cyclopentanecarbothioic acid ester                  273  40   N-methyl-L-proline                                                                      167, 270                                                                            [(S)(R*,R*)]-S-[2-Oxo-1-[4-(1-                                                pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl] 1-methyl-2-                                                     pyrrolidinylcarbothioic acid ester                  274  41   tetrahydro-3-                                                                           167, 270                                                                            S-Tetrahydro-3-furancarbothioic acid                          furoic acid     [2-oxo-1-[4-(1-pyrrolidinyl)-2-                                               butynyl]-3-pyrrolidinyl ester                       275  41   p-anisic acid                                                                           167, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                         butynyl]-3-pyrrolidinyl] 4-methoxy-                                           phenylcarbothioic acid ester                        276  40   p-anisoyl chloride                                                                      88    (S)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                         butynyl]-3-pyrrolidinyl] 4-                                                   methoxyphenylcarbothioic acid ester                 277  41   4-fluorophenyl                                                                          167, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         acetic acid     butynyl]-3-pyrrolidinyl] 4-                                                   fluorophenylethanethioic acid ester                 278  41   4-methoxyphenyl                                                                         167, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         acetic acid     butynyl]-3-pyrrolidinyl] 4-methoxy-                                           phenylethanethioic acid ester                       279  41   2-furoyl chloride                                                                       88    (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                         butynyl]-3-pyrrolidinyl] 2-furane-                                            carbothioic acid ester                              280  41   5-methyl-2-                                                                             167, 88                                                                             (R)-5-Methylpyrazinecarbothioic acid,                         pyrazine        S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                             carboxylic acid butynyl]-3-pyrrolidinyl] ester                      281  41   2-pyridylacetic                                                                         167, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         acid            butynyl]-3-pyrrolidinyl] pyridine-2-                                          ethanethioic thioic acid ester                      282  41   1-methyl-2-                                                                             167, 88                                                                             (R)-1-Methyl-1H-pyrrole-2-                                    pyrroleacetic acid                                                                            ethanethioic acid, S-[2-oxo-1-[4-(1-                                          pyrrolidinyl)-2-butynyl]-3-                                                   pyrrolidinyl] ester,                                283  41   2-thiopheneacetic                                                                       167, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         acid            butynyl]-3-pyrrolidinyl] thiophene-2-                                         ethanethioic acid ester                             284  41   3-thiopheneacetic                                                                       167, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         acid            butynyl]-3-pyrrolidinyl] thiophene-3-                                         ethanethioic acid ester                             285  41   4-pyridineacetic                                                                        167, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         acid            butynyl]-3-pyrrolidinyl] pyridine-4-                                          ethanethioic acid ester                             286  41   3-pyridineacetic                                                                        167, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         acid            butynyl]-3-pyrrolidinyl] pyridine-3-                                          ethanethioic acid ester                             287  41   cyclopentyl                                                                             88    (R)-O-Cyclopentylcarbonothioic acid,                          chloroformate   S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                             butynyl]-3-pyrrolidinyl] ester                      288  41   cyclohexyl                                                                              88    (R)-O-Cyclopentylcarbonothioic acid,                          chloroformate   S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                             butynyl]-3-pyrrolidinyl] ester                      289  41   cyclopentane-                                                                           185, 88                                                                             (R)-O-Cyclopentylmethylcarbonothioic                          methanol        acid, S-[2-oxo-1-[4-(1-pyrrolidinyl)-                                         2-butynyl]-3-pyrrolidinyl] ester                    290  41   tetrahydro-4H-                                                                          185, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         pyran-4-ol      butynyl]-3-pyrrolidinyl]carbonothioic                                         acid, O-(tetrahydro-2H-pyran-4-yl)                                            ester                                               291  41   tetrahydro-3-                                                                           185, 88                                                                             S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             furanemethanol  butynyl]-3-pyrrolidinyl]carbonothioic                                         acid, O-(tetrahydro-3-furanyl)methyl                                          ester                                               292  41   4-bromophenyl                                                                           88    (R)-O-(4-Bromophenyl)carbonothioic                            chloroformate   acid, S-[2-oxo-1-[4-(1-pyrrolidinyl)-                                         2-butynyl]-3-pyrrolidinyl] ester                    293  41   benzyl    88    (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         chloroformate   butynyl]-3-pyrrolidinyl]carbonothioic                                         acid, O-(phenylmethyl) ester                        294  41   2-thiophene                                                                             185, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         methanol        butynyl]-3-pyrrolidinyl]carbonothioic                                         acid, O-(2-thienyl)methyl ester                     295  41   2-(2-thienyl)                                                                           185, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         ethanol         butynyl]-3-pyrrolidinyl]carbonothioic                                         acid, O-[2-(2-thienyl)ethyl] ester                  296  41   3-(3-thienyl)                                                                           185, 88                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                         ethanol         butynyl]-3-pyrrolidinyl]carbonothioic                                         acid, O-[2-(3-thienyl)ethyl] ester                  297  41   cyclopentyl                                                                             88    (R)-Cyclopentylcarbamothioic acid,                            isocyanate      S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                             butynyl]-3-pyrrolidinyl] ester                      298  41   cyclohexyl                                                                              88    (R)-Cyclohexylcarbamothioic acid, S-                          isocyanate      [2-oxo-1-[4-(1-pyrrolidinyl)-2-                                               butynyl]-3-pyrrolidinyl] ester                      299  41   tetrahydrofuroic                                                                        253, 254, 88                                                                        (Tetrahydro-3-furanyl)carbamothioic                           acid            acid, S-[2-oxo-1-[4-(1-pyrrolidinyl)-                                         2-butynyl]-3-pyrrolidinyl] ester                    __________________________________________________________________________

The following Examples 300-312, found in Table XXI, are prepared by theprocedures listed.

                                      TABLE XXI                                   __________________________________________________________________________         Starting                                                                      Material       Procedure                                                 Example                                                                            Example        of                                                        No.  No.  Reagent   Example #                                                                           Name of Product                                     __________________________________________________________________________    300  41   p-anisoyl 254, 88                                                                             (R)-4-Methoxyphenylcarbamothioic acid,                        chloride        S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                             butynyl]-3-pyrrolidinyl] ester                      301  41   benzyl    88    (R)-2-Phenylmethylcarbamothioic acid, S-                      isocyanate      [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-                                      3-pyrrolidinyl] ester                               302  41   phenethyl 88    (R)-2-Phenylethylcarbamothioic acid, S-                       isocyanate      [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-                                      3-pyrrolidinyl] ester                               303  41   3-thiophene                                                                             253, 254,                                                                           (R)-3-Thienylcarbamothioic acid, S-[2-                        carboxylic acid                                                                         88    oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                       pyrrolidinyl] ester                                 304  41   3-thiopheneacetic                                                                       253, 254,                                                                           (R)-3-Thienylethanethioic acid, S-[2-                         acid      88    oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                       pyrrolidinyl] ester                                 305  41   2-thiopheneacetic                                                                       253, 254,                                                                           (R)-3-Thienylethanecarbamothioic acid,                        acid      88    S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                             butynyl]-3-pyrrolidinyl] ester                      306  41   dimethyl  88    (R)-N,N-Dimethylcarbamothioic acid, S-                        carbamoyl       [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl-                       chloride        3-pyrrolidinyl] ester                               307  41   diethyl carbamoyl                                                                       88    (R)-N,N-Diethylaminocarbamothioic acid,                       chloride        S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                             butynyl-3-pyrrolidinyl] ester                       308  41   N-methyl-N-phenyl                                                                       88    (R)-N-Methyl-N-phenylcarbamothioic acid,                      carbamoyl       S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                             chloride        butynyl-3-pyrrolidinyl] ester                       309  41   1-pyrrolidine                                                                           88    (R)-1-Pyrrolidinecarbothioic acid, S-                         carbonyl chloride                                                                             [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl-3-                                     pyrrolidinyl] ester                                 310  41   4-morpholine                                                                            88    (R)-4-Morpholinecarbothioic acid, S-[2-                       carbony chloride                                                                              oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                       pyrrolidinyl] ester                                 311  41   diphenyl  88    (R)-N,N-Diphenylcarbamothioic acid, S-                        carbamoyl       [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl-                       chloride        3-pyrrolidinyl] ester                               312  41   dibenzylcarbamoyl                                                                       88    (R)-N,N-Bis(phenylmethyl)carbamothioic                        chloride        acid, S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                       butynyl-3-pyrrolidinyl] ester                       __________________________________________________________________________

The following Examples 313-317, found in Table XXII, are prepared by theprocedures listed.

                                      TABLE XXII                                  __________________________________________________________________________         Starting                                                                      Material     Procedure                                                   Example                                                                            Example      of Example             M.P.                                 No.  No.    Reagent                                                                             #     Name of Product  °C.                           __________________________________________________________________________    313  Example 1                                                                            Ethyl 88    (R)-Ethylcarbamic acid, 2-oxo-1-(2-                                                            84-87                                     U.S. Pat. No.                                                                        isocyanate  propynyl)-3-pyrrolidinyl ester                             5,089,518                                                                314  Example 1                                                                            Ethyl 88    (S)-Ethylcarbamic acid, 2-oxo-1-(2-                                                            87-89                                     U.S. Pat. No.                                                                        isocyanate  propynyl)-3-pyrrolidinyl ester                             5,089,518                                                                315  Example 1                                                                            Butyl 88    (S)-Butylcarbamic acid, 2-oxo-1-(2-                                                            51-53                                     U.S. Pat. No.                                                                        isocyanate  propynyl)-3-pyrrolidinyl ester                             5,089,518                                                                316  Example 1                                                                            Ethyl 88    (S)-Hexylcarbamic acid, 2-oxo-1-(2-                                                            64-66                                     U.S. Pat. No.                                                                        isocyanate  propynyl-3-pyrrolidinyl ester                              5,089,518                                                                317  Example 1                                                                            Ethyl 88    (R)-Octylcarbamic acid, 2-oxo-1-                                                               70-72                                     U.S. Pat. No.                                                                        isocyanate  (2-propynyl)-3-pyrrolidinyl ester                          5,089,518                                                                __________________________________________________________________________

EXAMPLE 318

(R)-Ethylcarbamic acid1-[4-(dimethylamino)-2-butynyl]-2-oxo-3pyrrolidinyl ester

A solution of 2.2 g the product from Example 319, 0.93 g ofdimethylamine, 0.8 g of paraformaldehyde, 1.85 g of acetic acid 0.050 gof cuprous chloride in 50 ml od dioxane is heated at refluxtemperaturefor 45 min. The mixture is cooled and concentrated at reduced lopressure. The residue is basified with ammonium hydroxide and extractedwith methylene chloride. The methylene chloride solution is dried overanhydrous sodium sulfate, and concentrated at reduced pressure todryness. The resudue is purified (Alumina, Activity Grade 2.5: ethylacetate/hexane 1:1 (v/v)) to give the product as in Example 138.

The following Examples 319-320, found in Table XXIII, are prepared bythe procedures listed.

                                      TABLE XXIII                                 __________________________________________________________________________         Starting                                                                      Material      Procedure                                                  Example                                                                            Example       of                                                         No.  No.  Reagent  Example #                                                                           Name of Product                                      __________________________________________________________________________    319  313  2-(Methylamino)                                                                        88    (R)-Ethylcarbamic acid, 1-[4-[(2-                              ethanol        hydroxyethyl)methylamino]-2-butynyl]-                                         2-oxo-3-pyrrolidinyl ester                           320  313  4-(Methylamino)-                                                                       88    (R)-Ethylcarbamic acid, 1-[4-[(4-                              1-butanol      hydroxybutyl)methylamino]-2-butynyl]-                                         2-oxo-3-pyrrolidinyl ester                           __________________________________________________________________________

We claim:
 1. A compound of Formula I ##STR16## wherein R₃ is (C₂-C₁₀)alkanoyloxy, (C₃ -C₇)cycloalkylcarbonyloxy, (C₃ -C₇)cycloalkylcarbonyloxy, aroyloxy, aryl(C₁ -C₄)alkylcarbonyloxy, (C₁-C₁₀)alkoxycarbonyloxy, (C₃ -C₇)cycloalkoxycarbonyloxy, (C₃-C₇)cycloalkyl carbonyloxy, aryloxycarbonyloxy, aryl(C₁-C₄)alkyloxycarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy, (C₃-C₇)cycloalkylaminocarbonyloxy, (C₃ -C₇)cycloalkylaminocarbonyloxy,arylaminocarbonyloxy, aryl(C₁ -C₄)alkylaminocarbonyloxy, (C₁-C₁₀)dialkylaminocarbonyloxy, arylaminocarbonyloxy, (C₃-C₇)cycloalkyl(C₁ -C₄)alkylaminocarbonyloxy, diarylaminocarbonyloxy, andbis aminocarbonyloxy, in which any aryl group is phenyl, 2-naphthyl or4-biphenyl, andR4 is hydrogen or (C₁ -C₆)alkyl, or a pharmaceuticallyacceptable salt thereof.
 2. A compound of Formula I of claim 1 ##STR17##wherein R₃ is (C₂ -C₁₀)alkanoyloxy, (C₁ -C₁₀)alkoxycarbonyloxy, (C₁-C₁₀)alkylaminocarbonyloxy,andR₄ is hydrogen or (C₁ -C₃)alkyl, or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 1, (S)-Octanoic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1, (S)-Decanoic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 5. A compound according toclaim 1, (S)-Ethylcarbamic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1, (S)-Butylcarbamic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 7. A compound according toclaim 1, (S)-Hexylcarbamic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 8. A compound according toclaim 1, (S)-Octylcarbamic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 9. A compound according toclaim 1, (S)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinylcarbonic acid ethyl ester, or a pharmaceutically acceptable saltthereof.
 10. A compound according to claim 1,(S)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl carbonic acidbutyl ester, or a pharmaceutically acceptable salt thereof.
 11. Acompound according to claim 1,(S)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl carbonic acidoctyl ester, or a pharmaceutically acceptable salt thereof.
 12. Acompound according to claim 1, (R)-Octanoic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 13. A compound according toclaim 1, (R)-Ethylcarbamic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 14. A compound according toclaim 1, (R)-Butylcarbamic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 15. A compound according toclaim 1, (R)-Hexylcarbamic acid2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl ester, or apharmaceutically acceptable salt thereof.
 16. A compound according toclaim 1, (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinylcarbonic acid ethyl ester, or a pharmaceutically acceptable saltthereof.
 17. A compound according to claim 1,(R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl carbonic acidbutyl ester, or a pharmaceutically acceptable salt thereof.
 18. Acompound accoridng to claim 1,(R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl carbonic acidhexyl ester, or a pharmaceutically acceptable salt thereof.
 19. A methodof treating central cholinergic dysfunction in a mammal which comprisesadministering to said mammal an effective amount of a compound ofclaim
 1. 20. A pharmaceutical composition of matter in dosage unit formconprising from about 1 to about 500 mg of a compound of claim 1, inassociation with a pharmaceutically acceptable carrier.